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C3a is Required for ILC2 Function in Allergic Airway Inflammation
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A5945 - C3a is Required for ILC2 Function in Allergic Airway Inflammation
Author Block: N. Gour1, U. Smole2, H. M. Yong2, S. Lajoie2; 1Neuroscience, Johns Hopkins University, Baltimore, MD, United States, 2Environmental Health and Engineering, Johns Hopkins University, Baltimore, MD, United States.
RATIONALE: Allergic diseases are increasing worldwide, imposing a major healthcare burden. Type 2 responses drive the pathophysiology seen in allergic diseases like asthma, yet our understanding of the mechanisms leading to these aberrant immune responses remains limited. Recent evidence suggests that dysregulated innate immune factors can perpetuate asthma pathogenesis. C3a, an anaphylatoxin, one of the most ancient innate immune mediators, is elevated in asthmatics and is necessary to establish Th2 responses. Remarkably, the mechanisms by which C3a directly regulates type 2 immunity are relatively unknown. The contribution of C3a signaling in myeloid (DCs) cells in driving type 2 immunity appears to be negligible. We sought to determine if C3a could directly modulate the functionality of type 2 innate lymphoid cells 2 (ILC2), which have been recently shown to promote allergic responses in the lungs. METHODS: We exposed wildtype and C3a receptor (C3ar1)-deficient mice to allergen or rIL-33 (Type-2 promoting cytokine), and evaluated the allergic phenotype. In addition, we evaluated the functionality of flow-sorted wildtype and C3ar1-deficient ILC2 in the context of ILC-T cell crosstalk.RESULTS: We demonstrate a key role for C3a in promoting pulmonary ILC2 responses, downstream of allergen and IL-33. While C3a does not regulate the proliferation of ILC2, it is essential for the recruitment of ILC2 in the lungs. Further, we show that ILC2 directly respond to C3a, and this promotes Th2 immunity specifically by: 1) inducing IL-13 production from ILCs; and 2) enhancing their antigen-presenting capability during ILC-T cell crosstalk.CONCLUSIONS: Overall, we identify a novel mechanism by which C3a can mediate aberrant type 2 responses to aeroallergen exposure, which involves a previously unrecognized crosstalk between two major innate immune components - complement and ILC2.
Author Block: N. Gour1, U. Smole2, H. M. Yong2, S. Lajoie2; 1Neuroscience, Johns Hopkins University, Baltimore, MD, United States, 2Environmental Health and Engineering, Johns Hopkins University, Baltimore, MD, United States.
RATIONALE: Allergic diseases are increasing worldwide, imposing a major healthcare burden. Type 2 responses drive the pathophysiology seen in allergic diseases like asthma, yet our understanding of the mechanisms leading to these aberrant immune responses remains limited. Recent evidence suggests that dysregulated innate immune factors can perpetuate asthma pathogenesis. C3a, an anaphylatoxin, one of the most ancient innate immune mediators, is elevated in asthmatics and is necessary to establish Th2 responses. Remarkably, the mechanisms by which C3a directly regulates type 2 immunity are relatively unknown. The contribution of C3a signaling in myeloid (DCs) cells in driving type 2 immunity appears to be negligible. We sought to determine if C3a could directly modulate the functionality of type 2 innate lymphoid cells 2 (ILC2), which have been recently shown to promote allergic responses in the lungs. METHODS: We exposed wildtype and C3a receptor (C3ar1)-deficient mice to allergen or rIL-33 (Type-2 promoting cytokine), and evaluated the allergic phenotype. In addition, we evaluated the functionality of flow-sorted wildtype and C3ar1-deficient ILC2 in the context of ILC-T cell crosstalk.RESULTS: We demonstrate a key role for C3a in promoting pulmonary ILC2 responses, downstream of allergen and IL-33. While C3a does not regulate the proliferation of ILC2, it is essential for the recruitment of ILC2 in the lungs. Further, we show that ILC2 directly respond to C3a, and this promotes Th2 immunity specifically by: 1) inducing IL-13 production from ILCs; and 2) enhancing their antigen-presenting capability during ILC-T cell crosstalk.CONCLUSIONS: Overall, we identify a novel mechanism by which C3a can mediate aberrant type 2 responses to aeroallergen exposure, which involves a previously unrecognized crosstalk between two major innate immune components - complement and ILC2.
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