Sensing the world and its dangers: An evolutionary perspective in neuroimmunology

  1. Aurora Kraus
  2. Katherine M Buckley
  3. Irene Salinas  Is a corresponding author
  1. Department of Biology, University of New Mexico, United States
  2. Department of Biological Sciences, Auburn University, United States
3 figures and 1 table


Hypothetical pathways that lead to the emergence of NICUs in early metazoans.

(A) An ancient metazoan cell under microbial pressure acquires ion channels gaining the ability to detect danger (Elkhatib et al., 2019; Senatore et al., 2016). Eventually neuropeptides that have antimicrobial functions are released in response to microbes (Augustin et al., 2017). Innate immune cells gain neuropeptide receptors that trigger cytokine release (Pinho-Ribeiro et al., 2017). Finally, neuronal cells gain the ability to detect and respond to immune signaling cytokines (Chatterjea and Martinov, 2015; Chu et al., 2020). (B) An ancient metazoan cell acquires pattern recognition receptors and gains the ability to detect microbes (Boller and Felix, 2009; Rosenstiel et al., 2009). Eventually soluble immune mediators are released in response that trigger antimicrobial functions (Hanson et al., 2019). Neurons gain immune ligand receptors that trigger neuropeptide release (Lezi et al., 2018). Finally, immune cells gain the ability to detect and respond to neuronally derived neuropeptides (Chu et al., 2020; Foster et al., 2017). (C) An ancient metazoan cell under microbial pressure acquires pathogen pattern recognition receptor pathways concurrently with acquisition of ion channels that, under selective pressure gain the ability to detect danger (Tian et al., 2019). Eventually soluble neuroimmune mediators are secreted in response to pathogens modulate functions of neuronal and immune systems.

Emergence of the immune and nervous systems predates the emergence of Metazoa.

Analysis of genome sequences indicates that much of the cellular machinery involved in extant nervous and immune systems was present in basal metazoan lineages. This includes ion channels, pattern recognition receptors, and antimicrobial peptides (Franzenburg et al., 2012; Rosenstiel et al., 2009; Senatore et al., 2016). The evolutionary origin of significant innovations is indicated by dots (immune system in orange; nervous system in purple). Centralization of nervous systems within bilaterian phyla is indicated by small brain icons. Note CNS structures may be very diverse among invertebrate groups. Asterisk indicates possible independent, convergent evolution of Ctenophore neurons, a current point of debate (Moroz et al., 2014).

Schematic diagram illustrating how neurons play a role in the regulation of each step of the immune response, from inception to resolution.

(A) Sensory neurons detect danger cues that are then transduced to move the animals away from potential deleterious infection. For example, in C elegans npr-1 expressing neurons detect oxygen levels to avoid harmful pathogens (Hoffman and Aballay, 2019; Singh and Aballay, 2019; Styer et al., 2008). Furthermore, bacterially infected female Drosophila will lay fewer eggs (Kurz et al., 2017; Masuzzo et al., 2019). (B) Sensory neurons directly detect pathogen presence resulting in rapid action potentials and release of neurotransmitters that increase the velocity of an immune response. Neurons ultra-rapid communication to immune cell reservoirs deploy immune cells quicker than chemokine signals; such as recruiting CD8+ cells to the olfactory organ after detection of neurotrophic virus by sensory neurons (Chavan and Tracey, 2017; Sepahi et al., 2019). The immune responses triggered by neurons can be biased to be neuroprotective while dealing with infection such as in the myenteric plexus of the gut where b2 adrenergic receptor signaling polarizes muscularis macrophages to express Arg1, associated with an M2 phenotype (Gabanyi et al., 2016; Lai et al., 2020). (C) Pathogens detected by immune and epithelial cells provoke release of cytokines and other immune factors that are pro-inflammatory and potentially deleterious to the tissue if allowed to propagate inflammation without regulation. Local neurons are rapidly activated by the inflammatory environment and PAMPs, releasing neurotransmitters that tune the immune response (immune cells and epithelial cells) toward a less pro-inflammatory phenotype (Baral et al., 2018; Basbaum et al., 2009; Cardoso et al., 2017; Chu et al., 2020; Labed et al., 2018; Ramirez et al., 2020). A specific example is neuromedin U that binds to its cognate receptor on ILC2s enhancing their type 2/repair phenotype mediating protection against worm infections (Cardoso et al., 2017). Another example includes the reduction of systemic inflammation when the vagus nerve is stimulated (Borovikova et al., 2000). However, suppressive neuronal responses can be detrimental and favor infection as when TRPV1 neurons release CGRP and suppress neutrophil recruitment, leading to S. pyogenes lesion progression compared to animals lacking CGRP signaling (Pinho-Ribeiro et al., 2017; Chu et al., 2020). (D) The immune system and nervous system must balance their responses over time to return to homeostasis (Aurora and Olson, 2014; Veiga-Fernandes and Artis, 2018). An initial immune response is necessary for clearance of pathogen and debris and to initiate growth factor responses in neurons, but prolonged inflammation can be detrimental to neuronal regeneration as seen in the olfactory system and spinal cords with NF-κb/chemokine and TNFα signaling, respectively, leading to loss of regenerative abilities (Chen et al., 2019a; Godwin et al., 2013; Tsai et al., 2019; Tsarouchas et al., 2018). Another example includes the resolution of inflammation controlled by the sympathetic nervous system in mice (Körner et al., 2019).


Table 1
Molecules with dual roles in the immune and nervous systems.
Factors classically associated with immune functions
ProteinImmune system propertiesNervous system propertiesReferences
Antimicrobial peptides (AMPs)
  • Secreted by epithelial and phagocytic cells

  • Disrupt microbial membranes leading to destruction of pathogen

  • Antimicrobial in nervous system niches

  • Control chemotaxis of immune cells and astroglia

  • Mediate iron homeostasis

  • Modulate nerve impulses

  • Implicated in aging and neurodegeneration

Hanson et al., 2019; Lezi et al., 2018; Su et al., 2010; Zasloff, 2002
  • Produced by all leukocytes

  • Regulates hemocyte proliferation

  • Generally anti-inflammatory

  • Inhibits B cell proliferation

  • Influences development of Tregs and TH17 cells

  • Produced by neurons

  • Controls feeding behavior

  • Angio-suppressive roles in the brain

  • Regulates neuronal development and axon outgrowth

Arnold et al., 2014; Arrieta-Bolaños et al., 2012; Eisenstein and Williams, 2009; Hirota et al., 2015; Makhijani et al., 2017; Morishima et al., 2009; Singh and Aballay, 2019; Yi et al., 2010; You et al., 2008; Zheng et al., 2006
IL-4, IL-13
  • Induce TH2 antiparasitic immunity, tissue repair, allergic responses

  • Regulate spatial learning and neurogenesis

  • Bias astrocytes and microglia toward M2/neuroprotective states

  • Mediate oligodendrocyte growth and re-myelination

Fallon et al., 2002; Gadani et al., 2012; Kolosowska et al., 2019; McKenzie et al., 1998; Yang et al., 2016; Zhang et al., 2019a
  • Pro-inflammatory functions

  • Expressed in neurons after damage for acute protection

  • Long-term presence in the CNS is associated with decreased proliferation and neurogenesis

  • Alters permeability of the blood-brain barrier

  • Induces changes in sleep behavior

Borsini et al., 2015; Lambertsen et al., 2009; Liu et al., 1994; Takei and Laskey, 2008; Vanderheyden et al., 2018
Complement System ProteinsComplement factors
  • Opsonize pathogens for activation of innate and adaptive immune cells

  • Anti-inflammatory roles during CNS infection

  • Regulate synaptic pruning of microglia expressing C3 receptor

  • Regulate adult neurogenesis by causing increased maturation and migration of progenitors in SVZ and dentate gyrus

Hammad et al., 2018; Nonaka, 2001; Rupprecht et al., 2007; Shinjyo et al., 2009; Stevens et al., 2007
Perforin-like factors
  • Pore-forming proteins released by cytotoxic leukocytes

  • Form the membrane attack complex

  • ASTNs and BRINPs are expressed in CNS and associated with neurodevelopment

Ni and Gilbert, 2017
Pattern Recognition ReceptorsToll-like receptors (TLRs)
  • Detect extra- and intracellular pathogen and danger associated molecular patterns.

  • Regulate neuronal development, dendrite/axon growth and synapse formation

  • Recognize neurotrophins

  • Sensitize nociceptive neurons

Chen et al., 2019c; Donnelly et al., 2020; Foldi et al., 2017; Franzenburg et al., 2012; Lemaitre et al., 1996
Nod-like receptors (NLRs)
  • Detect intra-cellular pathogen and danger associated molecular patterns.

  • Immunomodulate glial cells

  • Prevents necrosis of neurons

Gharagozloo et al., 2017
Peptidoglycan recognition protein LC (PGRP-LC)
  • Detects peptidoglycan

  • Controls presynaptic homeostasis

Harris et al., 2015
Formyl peptide receptors (FPRs)
  • Expressed on macrophages

  • Detect pathogens and induce inflammation

  • Vomeronasal sensory neurons receptors

Dietschi et al., 2017
  • Released by mast cells

  • Mediates vasodilation and itch

  • Modulates neurogenic inflammation and nociceptive inflammation and has been implicated in migraines

  • Induces NGF expression by peripheral nociceptors

Yuan and Silberstein, 2018
Factors classically associated with neuronal functions
Transient receptor potential (TRPs)
  • Expressed by lymphocytes, dendritic cells, neutrophils, monocytes, macrophages, and mast cells.

  • Cause changes in intracellular Ca2+, which influences cell migration, cytokine production, phagocytosis and proliferation

  • Expressed by distinct subsets of sensory cells

  • Mediate neuronal depolarization and release of CGRP

Alpizar et al., 2017; López-Requena et al., 2017; Parenti et al., 2016
Nerve growth factor (NGF)
  • Released by mast cells, B lymphocytes.

  • Increases during inflammation

  • Receptor (TrkA) is expressed throughout immune system

  • Transduced NGF signal is anti-inflammatory

  • Stimulates growth, survival, and differentiation of neurons

Minnone et al., 2017; Pinho-Ribeiro et al., 2017; Takei and Laskey, 2008
Brain-derived neurotrophic factor (BDNF)
  • Implicated in lymphocyte development and survival

  • Regulates neuron growth, survival and synapse modulation

Fauchais et al., 2008; Lee et al., 2012; Linker et al., 2015; Schuhmann et al., 2005
Olfactory receptors
  • Activate pulmonary macrophage motility and CCL2 expression

  • Highly expressed in secondary lymphoid organs

  • Detect chemical odorants

Heimroth et al., 2020; Li et al., 2013
Calcitonin gene related peptide (CGRP)
  • An anti-inflammatory cytokine that promotes type 2 immunity

  • Decreases antigen presentation by MHC II, and inflammatory cytokine expression

  • Increases expression of the anti-inflammatory cytokine IL-10

  • Potent vasodilator

  • Released by T and B lymphocytes

  • Mediates pain transduction by nociceptors

  • Regulates regeneration of peripheral neurons

Chung, 2017; Kerage et al., 2019; Pinho-Ribeiro et al., 2017; Xu et al., 2019
Substance P
  • Secreted by microglia, T cells, macrophages, dendritic cells and eosinophils

  • Affects cytokine expression by binding to neurokinin receptor

  • Neuropeptide involved in nociception and neuroinflammation as well as hypotension and muscle contraction

Mashaghi et al., 2016
  • Lymphocytes and myeloid cells express the dopamine receptor

  • Enhances lymphocyte chemotaxis and maturation

  • Produced by dendritic cells

  • Neurotransmitter

Kerage et al., 2019; Matt and Gaskill, 2020
  • Acts as a pattern recognition receptor that mediates phagocytosis in arthropods

  • Regulates axon/dendrite segregation during neuronal development

Goyal et al., 2019; Hattori et al., 2009; Ng and Kurtz, 2020
  • Present on NK cells, activated T cells and other cytotoxic cell subsets

  • Neuronal cell migration and synaptic plasticity

Van Acker et al., 2017; Vukojevic et al., 2020
  • Exocytosis of perforins, granzymes, and cytokines

  • Exocytosis of neurotransmitters

Ramakrishnan et al., 2012; Tang, 2015

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  1. Aurora Kraus
  2. Katherine M Buckley
  3. Irene Salinas
Sensing the world and its dangers: An evolutionary perspective in neuroimmunology
eLife 10:e66706.