Inflammation is an immune response that helps the body to repair damaged tissues and defend itself against bacteria and other harmful microbes. Immune cells called macrophages stimulate inflammation when they detect bacteria and other microbes. However, the strength of the inflammatory response is tightly controlled to prevent too much inflammation when it is not necessary. There is evidence that an inability to control the activity of macrophages can lead to excessive inflammation that can in itself cause injury.

Inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, occur when the intestine becomes inflamed in response to the bacteria that normally live there. Most patients with these diseases first present symptoms as young adults, but in rare cases the symptoms appear during infancy. Some patients who develop symptoms early in life carry a mutation in a gene encoding IL10R, a receptor protein that normally inhibits the ability of macrophages to cause inflammation. However, it was not known exactly when the inflammation begins in infants.

Mice are often used in research as models of human health and disease. Redhu et al. investigated the role of IL10R in the intestines of infant mice. These experiments showed that the intestines of mutant mice that lacked the IL10R protein became inflamed as they were weaned from breast milk to a solid diet. This inflammation was accompanied by a greater increase in the number of actively recruited macrophages in the intestine of mutant mice compared to normal mice. Further experiments revealed that macrophages in the mutant mice activate many genes involved in inflammation. The transition from breast milk to a solid diet is accompanied by large increases in intestinal bacteria. Treating the mice with antibiotics decreased the number of bacteria in the intestines and reduced the level of inflammation, as did treating the mice with a compound that killed macrophages.

The findings of Redhu et al. suggest that IL10R prevents macrophages from causing inflammation when infant mice are weaned. This, in turn, suggests that treatments that modify intestinal macrophages, as well as bacteria, could help infants that have, or are at risk of developing inflammatory bowel disease. In the longer-term, these findings might also aid the development of new treatments for older patients with inflammatory bowel diseases.

Inflammatory bowel diseases (IBD) including Crohn’s disease (CD) and ulcerative colitis (UC) are thought to result from the interaction of microbial and environmental factors with a genetically susceptible host. While IBD susceptibility is generally considered to arise from complex genetic risk in adolescent and adult patients, those who develop symptoms during infancy (age <2), or before 6 years of age (very early onset IBD, VEOIBD), often present with disease refractory to conventional therapies and are more likely to have disease-causative single gene mutations (Uhlig et al., 2014). A detailed understanding of disease pathogenesis in infants, as well as model systems that recapitulate infantile-onset IBD, may lead to fundamental insights into the etiology of IBD, and identify novel therapeutic strategies. In this regard, rare loss-of-function mutations in IL10, or its receptors IL10RA or IL10RB in humans lead to infantile onset IBD (Glocker et al., 2010, 2009; Moran et al., 2013; Shouval et al., 2014a; Kotlarz et al., 2012), suggesting that the IL10/IL10R pathway is essential for intestinal mucosal homeostasis and prevention of intestinal inflammation in infancy. Thus, modeling infantile-onset colitis in mice that lack functional IL10R signaling could lead to significant advances in our understanding of the etiopathogenesis of these diseases.

IL10 is a potent anti-inflammatory cytokine that inhibits proinflammatory and co-stimulatory function in both innate and adaptive immune cells (Ding and Shevach, 1992; Fiorentino et al., 1991; Saraiva and O'Garra, 2010). Like humans, mice deficient in IL10 or the IL10R on the 129SvEv background develop chronic spontaneous colitis (Kang et al., 2008; Kühn et al., 1993; Spencer et al., 1998), strongly supporting the concept that IL10 signaling plays a central role in preventing mucosal inflammation. These murine models have enabled investigations into the cellular and microbial factors that contribute to the development of IBD. However, because colitis in these models presents after an extended latency, understanding the developmental events early in life that contribute to disease development remain to be defined.

The IL10 receptor (IL10R) is a heterotetramer consisting of two chains of ligand-binding IL10Rα (IL10R1) and two subunits of signaling IL10Rβ (IL10R2) (Donnelly et al., 2004; Moore et al., 2001). The IL10R is expressed on cells of both the innate and adaptive immune compartments and a number of studies have highlighted the role of IL10R on subsets of regulatory T cells and T helper 17 (Th17) cells in preventing the development of colitis (Chaudhry et al., 2011; Huber et al., 2011; Kamanaka et al., 2011; Murai et al., 2009). Recently, we and others have demonstrated a requirement for IL10R in innate immune cells to prevent murine colitis (Li et al., 2015; Shouval et al., 2014b, 2016; Zigmond et al., 2014). In addition, we have shown excessive accumulation of inflammatory Ly6C⁺ monocytes within the colons of colitic IL10R-deficient mice as well as defects in the differentiation of both murine and human anti-inflammatory macrophages (MΦs) defective in IL10R signaling (Shouval et al., 2014b). It has previously been shown that intestinal microbiota promotes the accumulation of Ly6C⁺ monocytes within the lamina propria (LP) (Bain et al., 2014) and there is ample evidence that the microbiota is intimately involved in the development of colitis in many susceptible mouse models including mice lacking IL10 signaling (Kang et al., 2008; Sellon et al., 1998). Taken together, these studies imply that IL10R signaling on intestinal MΦs prevents microbially-driven recruitment of Ly6C⁺ monocytes and the development of intestinal inflammation.

While the studies outlined above demonstrate the critical role of IL10R signaling within MΦs in preventing inflammatory responses in the large intestine, the colitis that develops spontaneously in mice that are completely-deficient in IL10R or that specifically lack IL10R within CX3CR1⁺ MΦs manifest with a prolonged latency of several weeks, and is strain- and microbiota-dependent (Kang et al., 2008; Kühn et al., 1993; Spencer et al., 1998; Zigmond et al., 2014). Given that colitis in infants lacking functional IL10R is an aggressive disease that presents very early in life (Glocker et al., 2009; Shouval et al., 2014a), it is unclear whether the same cellular mechanisms observed in adult mice lacking IL10R are in fact operating within the time frame of infant development. Furthermore, it has not been determined whether specific developmental events during the post-partum period such as initial bacterial colonization at the time of birth, or the diversification of the infant microbiome that occurs at the time of weaning are influenced by the absence of IL10R and/or play catalytic roles in driving inflammation in the absence of IL10R.

To address these issues, we performed detailed time-series experiments using IL10R-deficient infant mice and their littermate co-housed controls, and evaluated histology, inflammatory gene expression, cellular composition of the LP, and luminal bacterial communities from birth to 14 weeks of age. We used clodronate depletion to investigate the role of colonic MΦs in colonic inflammation that develops in infant IL10R-deficient mice. In addition, we analyzed the onset of colitis in crosses between C57BL/6 mice lacking IL10Rα specifically in MΦs and those carrying a genetic locus driving colitis susceptibility, Cdcs1, neither of which independently develop colitis. Our data demonstrate that the requirement for macrophage-intrinsic IL10R signaling develops during a critical developmental transition, which has important implications for understanding factors that initiate colitis in infants with genetic deficiencies in IL10R signaling.

IBD including CD and UC typically present during adolescence and early adulthood. However, rare patients with causative single gene defects can present in infancy (age <2), or at an age less than 6 years (VEOIBD) (Uhlig et al., 2014). A prime example of this is IL10R deficiency which often presents in the first 2 years of life (Shouval et al., 2014a; Glocker et al., 2011). However, because commonly used mouse models lacking IL10R signaling do not exhibit overt signs of colitis until adulthood, there is a paucity of information regarding requirements for IL10R signaling during infancy. Given the rapid developmental changes in intestinal physiology, immune system responsiveness, diet, and the microbiome that occur during the first weeks of life (Arrieta et al., 2014; Pantoja-Feliciano et al., 2013), characterizing the function of IL10R signaling during this period could reveal fundamental regulatory processes that are essential to preventing IBD in infancy, and may aid our understanding of the pathological mechanisms driving IBD in general. To this end, we have provided a detailed analysis of the function of IL10R signaling during infant development using a series of genetically modified mice.

Here we demonstrate that although there are no signs of inflammation within the intestine of IL10R-deficient mice less than 14 days of age, IL10R is required to prevent an intestinal inflammatory response that emerges during the third week of life. Consistent with previous work suggesting that IL10R signaling in MΦs prevents excessive lower bowel inflammation in various models (Li et al., 2015; Shouval et al., 2014b; Zigmond et al., 2014), the onset of intestinal inflammation in 3 week old Il10rb^-/- mice was associated with increased numbers of LP MΦs, as well as an inversion in the ratio of newly recruited P1/P2 MΦ populations and resident P3/P4 MΦs. Further, while resident P3/P4 MΦs typically exhibit an anti-inflammatory phenotype, RNA-seq analyses indicated that the anti-inflammatory phenotype of IL10R-deficient LP MΦs was compromised at the onset of inflammation, suggesting that altered MΦ phenotype had a causative role in initiating the inflammatory process. In contrast to a clear alteration in LP MΦ phenotype between 2 and 3 week old IL10R-deficient mice, significant alterations in effector T cell populations were not consistently observed. Consistent with a key role for MΦs, we found that clodronate-mediated depletion of MΦs inhibited colitis, and that the lack of IL10Rα specifically on MΦs led to the development of aggressive colitis in 3–4 week old C57BL/6 Cdcs1 congenic mice. Interestingly, while treatment with antibiotics suppressed inflammation in 3–4 week old mice lacking the IL10R, we found no evidence that IL10R regulated microbiota composition during infancy. These results strongly support a model in which IL10R signaling is required on MΦs to prevent a microbiota-driven inflammatory response that develops during the third week of infant life. Understanding the factors that drive this response, and delineating how IL10 inhibits this, could uncover essential pathways that regulate the development of intestinal inflammation in infants.

A central question raised by this study is why colonic inflammation in IL10R-deficient mice is first detected in the third week of life. Certainly, one of the most obvious changes in this time frame is the transition from breast milk to solid food, with the concomitant introduction of complex dietary carbohydrates. Multiple aspects of physiology change at the time of weaning (weaning transition), including rapid expansion of the microbiota, alterations in intestinal metabolites (Arrieta et al., 2014; Pantoja-Feliciano et al., 2013; Blacher et al., 2017; Torow et al., 2017), and the replacement of yolk-sac derived intestinal MΦs with MΦs derived from circulating monocytes (Bain et al., 2014). While hard-wired developmental programs may underlie some aspects of these events, it is conceivable that preventing access to solid food may interfere with expansion of the microbiota observed at the time of weaning, and further that the presence of intestinal microbiota catalyzes the replacement of yolk-sac derived intestinal MΦs with monocyte-derived MΦs (Bain et al., 2014). Thus, the weaning transition appears to induce a series of events that remodels intestinal homeostasis, and in the process, activates a pathway whose inflammatory potential is held in check by IL10R signaling.

The role of microbiota in driving intestinal inflammation in immunodeficient strains is well appreciated, and it has been suggested that dysbiosis caused by underlying immune dysregulation may be sufficient to cause colitis in some situations (Garrett et al., 2007). While our studies are consistent with previous studies demonstrating that colitis in IL10-deficient mice is attenuated under germ-free conditions (Sellon et al., 1998), and that antibiotics can prevent colitis in mice lacking IL10Rβ, or those lacking IL10Rβ and concurrently expressing dnTGFβRII (Kang et al., 2008), the lack of dysbiosis in mice deficient in IL10R suggests that IL10 is not regulating the microbiome per se. Therefore, it appears unlikely that a direct effect of IL10R signaling on the microbiome is responsible for the colitis that develops in infant IL10R-deficient mice. In contrast, it was previously reported that IL10-deficient and WT mice exhibit significant differences in microbial diversity and composition (Maharshak et al., 2013). Differences between our results and these previous results might be due to differences in the experimental design, endogenous institutional microbiota, and the nature of the animals models used. For instance, in our study IL10R-deficient and control mice were born and co-housed under SPF condition, whereas in the prior study adult germ-free IL10-deficient and WT mice were recolonized with SPF microbiota and then housed separately (Maharshak et al., 2013). Nonetheless, the fact that loss in microbial diversity followed the increase in intestinal inflammation in IL10-deficient mice suggested that dysbiosis was a secondary event to inflammation in the IL10-deficient model (Maharshak et al., 2013). On the other hand, it is certainly possible that the increase in bacterial diversity that is observed at the weaning transition leads to colonization by microbes with augmented inflammatory potential compared to those present in the immediate post-natal period, such as the potential pathobiont H. ganmani, thereby revealing a requirement for IL10R signaling that was not present prior to weaning. Notably, it has been shown that colonization of germ-free IL10-deficient mice with H. hepaticus and Lactobacillus reuteri but not either species alone, led to severe typhlocolitis in germ-free IL10-deficient mice (Whary et al., 2011), indicating that colonization with a Gram-negative pathobiont (Helicobacter) in association with other microbes is sufficient to drive intestinal inflammation in susceptible murine strains, and raising the possibility that the expansion of H. ganmani in the context of other non-pathogenic flora is responsible for development of infantile colitis in our model. The previous observation that inflammation in Il10^-/- mice, positive for Helicobacter sp., is abrogated in mice specifically lacking the TLR signaling adaptor MyD88 in mononuclear phagocytes (Hoshi et al., 2012) indicates the likely importance of direct pathogen recognition, including that of Helicobacter sp. and potential other colitis-triggering microbes, for the development of intestinal inflammation in the absence of IL10R signaling.

The increase in microbial diversity observed at the weaning transition also coincides with the initiation of monocyte recruitment into the LP, and replacement of yolk sac-derived LP MΦs with monocyte-derived MΦs (Bain et al., 2014). It is unclear whether inflammation in infant Il10rb^-/- mice is driven by resident MΦs or the newly recruited monocyte-derived MΦs. The data from our clodronate experiments demonstrated that a phagocytic cell is responsible for driving inflammation in the infant IL10R-deficient mice but whether this is due to newly recruited monocyte/MΦs is an open question. Interestingly, while blocking monocyte recruitment by using a CCR2-neutralizing antibody (MC21) inhibited DSS-induced colitis (Zigmond et al., 2012), in a preliminary experiment we were unable to detect significant differences in the colonic expression of inflammatory genes including Il12b, Ifng, Tnf, and Il1b between isotype and MC21 antibody-treated 3 week old Il10rb^-/- mice despite markedly decreased infiltration of Ly6C⁺ cells (data not shown). Consistent with this preliminary experiment, it has previously been demonstrated that genetic loss of CCR2 did not reverse colonic inflammation in IL10-deficient mice (Hoshi et al., 2012). Notably, monocyte recruitment was not completely blocked in Il10^-/-Ccr2^-/- mice, suggesting that there might be alternate and potentially redundant mechanisms of monocyte recruitment (Hoshi et al., 2012) in these models, and therefore the question of exactly which clodronate-sensitive monocyte/MΦ population drives inflammation in IL10/IL10R deficiency remains open.

Although we did not perform lineage-tracing experiments, by evaluating macrophage phenotype in early infancy we have presumably examined the function of IL10R-deficient MΦs that are of yolk-sac origin. While it has been previously proposed that the function of yolk sac and monocyte-derived LP MΦs are quite similar (Bain et al., 2014), we were surprised to find that prior to the weaning transition, the gene expression profiles of LP MΦs of presumed yolk sac origin from IL10R-deficient mice closely matched gene expression profiles obtained from MΦs isolated from control mice, and lacked strong pro-inflammatory gene expression. These results suggest that LP MΦs of yolk sac origin maintain an anti-inflammatory state even in the absence of IL10R signaling. While the absence of an inflammatory phenotype in IL10R-deficient LP MΦs prior to weaning may be explained by exogenous factors such as difference in the microbiota or diet prior to and after weaning, it is also possible that this phenotype is a result of fundamental differences in MΦ lineages. Understanding the basis for differences in the phenotype of IL10R-deficient LP MΦs prior to and after weaning is an important line of future investigation, and should such studies suggest that there are intrinsic differences in the phenotype of IL10R-deficient LP MΦs prior to weaning, detailed analysis of transcriptional regulation in infant IL10R-deficient LP MΦs could reveal IL10R-independent pathways that inhibit MΦ inflammatory responses. Identification of these pathways could lead to novel therapeutic approaches to patients with defects in IL10R signaling.

While our study clearly demonstrates the importance of IL10R signaling on MΦs to prevent intestinal inflammation in the infant mouse, the exact mechanisms through which IL10 signaling inhibits inflammatory gene expression in LP MΦs is not completely understood. We have recently shown that IL10 rapidly inhibits LPS-induced enhancer activation in bone marrow-derived MΦs (Conaway et al., 2017), but do not yet know whether the absence of IL10R signaling influences the function of enhancers in LP MΦs. Further, it remains unclear whether the critical function of IL10R is to directly inhibit inflammatory gene expression in MΦs or alternatively to promote production of a factor with a broad inhibitory function. Although it is clear that IL10R signaling strongly inhibits a group of inflammation-induced genes, the ability of a relatively small number of adoptively transferred IL10R-sufficient MΦs to suppress the development of colitis in Rag2^-/-Il10rb^-/- mice reconstituted with CD4⁺ T cells (Shouval et al., 2014b) suggests that WT MΦs exert a dominant effect over IL10R-deficient MΦs. This type of effect is more compatible with a requirement for IL10R to induce production of an inhibitory factor than an intrinsic requirement to prevent inflammatory gene expression. Further studies using mixed radiation chimeras with congenically marked control and IL10R-deficient MΦs will be necessary to fully understand this issue.

Collectively, our data indicate that IL10R signaling in MΦs is pivotal in confining a microbiota-driven inflammatory response beginning at the third week of life. Alterations in colonic LP anti-inflammatory MΦ phenotype is a key early event initiating this inflammatory cascade. While further directed experiments are still needed to address the primary function of IL10R in resident colonic MΦs during infant development, it is enticing to speculate that the intestinal inflammation observed in infants lacking IL10R signaling may be based on the inability of host MΦs to control the inflammatory potential of the expanding intestinal microbiota. In short, our data has uncovered a critical ‘window of opportunity’ to further dissect the mechanism(s) leading to the development of infantile colitis.

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Author details

1. Naresh S Redhu

   1. Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, United States
   2. Harvard Medical School, Boston, United States

   Contribution

   NSR, Conceptualization, Data curation, Formal analysis, Investigation, Writing—original draft, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-0264-9925

2. Vasudevan Bakthavatchalu

   Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, United States

   Contribution

   VB, Data curation, Formal analysis, Investigation, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

3. Evan A Conaway

   Department of Pathology, Brigham and Women's Hospital, Boston, United States

   Contribution

   EAC, Investigation, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

4. Dror S Shouval

   1. Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, United States
   2. Division of Pediatric Gastroenterology and Nutrition, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel
   3. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

   Contribution

   DSS, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

5. Amy Tsou

   1. Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, United States
   2. Harvard Medical School, Boston, United States

   Contribution

   AT, Data curation, Formal analysis, Investigation, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

6. Jeremy A Goettel

   1. Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, United States
   2. Harvard Medical School, Boston, United States

   Contribution

   JAG, Formal analysis, Investigation, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

7. Amlan Biswas

   1. Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, United States
   2. Harvard Medical School, Boston, United States

   Contribution

   ABi, Formal analysis, Investigation, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0003-4299-1001

8. Chuanwu Wang

   Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, United States

   Contribution

   CW, Investigation, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

9. Michael Field

   Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, United States

   Contribution

   MF, Investigation, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

10. Werner Muller

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

    Contribution

    WM, Resources, Writing—review and editing

    Competing interests

    The authors declare that no competing interests exist.

11. Andre Bleich

    Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany

    Contribution

    ABl, Resources, Writing—review and editing

    Competing interests

    The authors declare that no competing interests exist.

12. Ning Li

    Department of Pathology, Massachusetts Host-Microbiome Center, Brigham and Women’s Hospital, Boston, United States

    Contribution

    NL, Formal analysis, Investigation, Writing—review and editing

    Competing interests

    The authors declare that no competing interests exist.

13. Georg K Gerber

    Department of Pathology, Massachusetts Host-Microbiome Center, Brigham and Women’s Hospital, Boston, United States

    Contribution

    GKG, Supervision, Methodology, Writing—review and editing

    Competing interests

    The authors declare that no competing interests exist.

    "This ORCID iD identifies the author of this article:" 0000-0002-9149-5509

14. Lynn Bry

    Department of Pathology, Massachusetts Host-Microbiome Center, Brigham and Women’s Hospital, Boston, United States

    Contribution

    LB, Supervision, Writing—review and editing

    Competing interests

    The authors declare that no competing interests exist.

15. James G Fox

    Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, United States

    Contribution

    JGF, Supervision, Methodology, Writing—review and editing

    Competing interests

    The authors declare that no competing interests exist.

16. Scott B Snapper

    1. Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, United States
    2. Harvard Medical School, Boston, United States
    3. Division of Gastroenterology, Brigham and Women's Hospital, Boston, United States

    Contribution

    SBS, Conceptualization, Resources, Formal analysis, Funding acquisition, Investigation, Methodology, Writing—review and editing

    For correspondence

    Scott.Snapper@childrens.harvard.edu

    Competing interests

    The authors declare that no competing interests exist.

17. Bruce H Horwitz

    1. Harvard Medical School, Boston, United States
    2. Department of Pathology, Brigham and Women's Hospital, Boston, United States

    Contribution

    BHH, Conceptualization, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing—original draft, Project administration, Writing—review and editing

    For correspondence

    bhorwitz@partners.org

    Competing interests

    The authors declare that no competing interests exist.

    "This ORCID iD identifies the author of this article:" 0000-0002-8123-8728

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