C3a is required for ILC2 function in allergic airway inflammation

Abstract

Aberrant type 2 responses underlie the pathologies in allergic diseases like asthma, yet, our understanding of the mechanisms that drive them remains limited. Recent evidence suggests that dysregulated innate immune factors can perpetuate asthma pathogenesis. In susceptible individuals, allergen exposure triggers the activation of complement, a major arm of innate immunity, leading to the aberrant generation of the C3a anaphylatoxin. C3 and C3a have been shown to be important for the development of Th2 responses, yet remarkably, the mechanisms by which C3a regulates type 2 immunity are relatively unknown. We demonstrate a central role for C3a in driving type 2 innate lymphoid cells (ILC2)-mediated inflammation in response to allergen and IL-33. Our data suggests that ILC2 recruitment is C3a-dependent. Further, we show that ILC2s directly respond to C3a, promoting type 2 responses by specifically: (1) inducing IL-13 and granulocyte-macrophage colony-stimulating factor, whereas inhibiting IL-10 production from ILC2; and (2) enhancing their antigen-presenting capability during ILC-T-cell cross-talk. In summary, we identify a novel mechanism by which C3a can mediate aberrant type 2 responses to aeroallergen exposure, which involves a yet unrecognized cross-talk between two major innate immune components-complement and group 2 innate lymphoid cells.

Complement and CD4+ T cells drive context-specific corneal sensory neuropathy

“…For this purpose, we utilized established murine models of allergic eye disease (AED) and ocular graft-versus-host disease (GVHD) (Herretes et al, 2015; Lee et al, 2015). Our rationale for this is that complement has been implicated in the etiology of systemic GVHD and allergic inflammation (Gour et al, 2018; Kwan et al, 2012; Ma et al, 2014; Nguyen et al, 2018; Zhang and Köhl, 2010). However, a neuroinflammatory role of complement has not been described for either disease within the eye.…”

Mice lacking fucosyltransferase 2 show reduced innate allergic inflammation in the airways

“…It is noteworthy that although the fraction of fucosylated lung epithelial cells is significantly increased upon IL-33 or papain stimulation, the UEA-I staining may underestimate its extent, because Tátrai et al reported that some parts of lung cells were inaccessible to UEA-I. 9 We also found that Fut2 deficiency is associated with reduced production of C3a, which has the capacity to enhance the recruitment and activation of ILC2s, 7…”

Enolase-specific cross antibodies induce neutrophilic inflammation in the intestine

“…Activated complements are associated with the pathogenesis of inflammation. C3a and C5a can induce anaphylactic mediators, such as histamine release and attract phagocytes to the sites 29,30 ; C5b‐9 induces target cell apoptosis 31 . These factors from complement activation are closely associated with the pathogenesis of inflammation 32 …”