Cytokines and beyond: Regulation of innate immune responses during helminth infection

Abstract

Parasitic helminth infection elicits a type 2 cytokine-mediated inflammatory response. During type 2 inflammation, damaged or stimulated epithelial cells exposed to helminths and their products produce alarmins and cytokines including IL-25, IL-33, and thymic stromal lymphopoietin. These factors promote innate immune cell activation that supports the polarization of CD4 T helper type 2 (Th2) cells. Activated innate and Th2 cells produce the cytokines IL-4, -5, -9, and -13 that perpetuate immune activation and act back on the epithelium to cause goblet cell hyperplasia and increased epithelial cell turnover. Together, these events facilitate worm expulsion and wound healing processes. While the role of Th2 cells in this context has been heavily studied, recent work has revealed that epithelial cell-derived cytokines are drivers of key innate immune responses that are critical for type 2 anti-helminth responses. Cutting-edge studies have begun to fully assess how other factors and pathways, including lipid mediators, chemokines, Fc receptor signaling, danger-associated molecular pattern molecules, and direct cell-cell interactions, also participate in shaping innate cell-mediated type 2 inflammation. In this review, we discuss how these pathways intersect and synergize with pathways controlled by epithelial cell-derived cytokines to coordinate innate immune responses that drive helminth-induced type 2 inflammation.

The Prostaglandin D2 Receptor CRTH2 Promotes IL-33–Induced ILC2 Accumulation in the Lung

“…The specificity of partially CRTH2-dependent IL-33-elicited cell accumulation in vivo to ILC2s compared with eosinophils and CD4 + T cells that express CRTH2 (20,39,45,46) (Supplemental Fig. 1G-I) speaks to the complexity of the type 2 inflammatory milieu in vivo.…”

“…Notably, the CRTH2-dependent ILC2 accumulation in the lung after multiple i.p. rmIL-33 treatments was cell type specific, as other cell types that express ST2 and/or CRTH2, such as eosinophils and CD4 + Th2 cells (20,39,45,46), accumulated equally in the lung in response to ongoing rmIL-33 i.p. treatment (Supplemental Fig.…”

“…Various mediators act on ILC2s to promote their activation and proliferation during type 2 inflammation (20)(21)(22). IL-33 is an epithelial-and myeloid cell-derived cytokine that is released during type 2 inflammation (23)(24)(25)(26).…”

Interleukin‐35 in immune‐related diseases: protection or destruction

“…Recent studies have uncovered a wealth of information on the role of cytokines in the regulation of immunomodulatory processes . Endogenous and exogenous cytokines play a variety of roles in maintaining the delicate balance of the immune system, and disruption of this equilibrium may lead to debilitating immune‐related diseases . In 2007, Collison et al .…”

“…2,3 Endogenous and exogenous cytokines play a variety of roles in maintaining the delicate balance of the immune system, and disruption of this equilibrium may lead to debilitating immune-related diseases. 4 In 2007, Collison et al 5 identified interleukin-35 (IL-35) as a novel inhibitory cytokine, consisting of Epstein-Barr virus-induced gene 3 (EBI3) and IL-12 subunit a chain (P35) subunits and belonging to the IL-12 cytokine family. Unlike other IL-12 family members, which are known to be primarily secreted by activated antigen-presenting cells, 6,7 IL-35 is primarily expressed in unstimulated regulatory T (Treg) cells in mice, but is not detected in the unstimulated human Treg cells.…”