Frontline Science: RIP2 promotes house dust mite–induced allergic airway inflammation

Abstract

House dust mites (HDMs) are one of the most significant environmental allergens in the establishment of the so-called "Atopic March." It is known that the immune response to HDM is Th2 dominant, but the innate mechanisms leading to HDM-induced type 2 responses are still not completely understood. A number of innate immune receptors have been implicated in the response to HDM including toll-like receptors, C-type lectin receptors, and protease activated receptors. NOD2 is a member of the NOD-like receptor family, which has been reported to be involved in the establishment of type 2 immunity and in blocking respiratory tolerance. NOD2 mediates its effects through its downstream effector kinase, receptor interacting protein (RIP2). It has not been shown if RIP2 is involved in the innate response to HDM and in the resulting generation of type 2 immunity. Furthermore, the role of RIP2 in modulating allergic airway inflammation has been controversial. In this study, we show that RIP2 is activated in airway epithelial cells in response to HDM and is important for the production of CCL2. Using a murine HDM asthma model, we demonstrate that lung pathology, local airway inflammation, inflammatory cytokines, HDM-specific IgG antibody production, and HDM-specific Th2 responses are all reduced in RIP2 knockout mice compared to WT animals. These data illustrate that RIP2 can be activated by a relevant allergic stimulus and that such activation can contribute to allergic airway inflammation. These findings also suggest that RIP2 inhibitors might have some efficacy in down-regulating the inflammatory response in type 2 dominated diseases.

Allergic asthma: RIPK2 takes the lead

“…5 However, the role of these cytoplasmic sensors in the development of allergic asthma remain poorly understood. In the current issue of Journal of Leukocyte Biology , Miller et al 6 demonstrate a central role for receptor-interacting protein kinase 2 (RIPK2) in promoting lung inflammation and allergic asthma in mice following sensitization with HDM ( Dermatophagoides farinae ), which is a common source of household allergen (Fig. 1).…”

“…7 In contrast, Ripk2 −/− mice on a C57BL/6 background show similar susceptibility to OVA-induced asthma when compared with C57BL/6 WT controls. 8 While differences in genetic background of mice could account for the observed differences in the function of RIPK2 during OVA-induced asthma; Miller et al 6 used HDM-induced asthma as a mouse model system to resolve the role of RIPK2. To induce airway inflammation and asthma, mice are intratracheally sensitized with 60 μ g HDM on day 0 followed by daily HDM challenge (37.5 μ g intratracheally) from days 7 to 11.…”

“…Overall, Ripk2 −/− mice show significant protection from HDM-induced airway inflammation when compared with C57BL/6 controls suggesting a central role for RIPK2 in driving inflammation and pathogenesis during asthma. 6 Nucleotide oligomerization domain (NOD) protein 1 and 2 (NOD1 and NOD2) are the cytoplasmic sensors that recruit RIPK2 to initiate signaling and so far, receptors other than NOD1 and NOD2 have not been described for RIPK2. 9 Studies comparing HDM-induced asthma in WT, Ripk2 −/− , Nod1 −/− , and Nod2 −/− mice will elucidate whether NOD1, NOD2, or both receptors are involved in the sensing of HDM to induce RIPK2-dependent allergic asthma.…”

“…10 Moreover, the kinase function of RIPK2 has not been well studied with most of the RIPK2 function in NOD1 and NOD2 signaling attributed to RIPK2 scaffold activity. Miller et al 6 demonstrate that HDM extract (250 PNU/ml of D. farina ) stimulation of human airway epithelial cell lines Calu3 and A549 induced acute RIPK2 tyrosine phosphorylation in vitro, suggestive of RIPK2 activation. However, the requirement of RIPK2 phosphorylation for RIPK2 function and activity needs further investigation.…”

“…Miller et al 6 propose that RIPK2 functions in the airway epithelial cells to regulate early chemokine/cytokine production that in-turn promotes Th2 immune responses during HDM exposure. HDM extract stimulation of human airway epithelial Calu3 cells induce robust expression of CCL2 mRNA, which is abolished in Calu3 cells with CRISPR/Cas9-mediated knockdown of RIPK2.…”