Small Proline-Rich Protein 3 Regulates IL-33/ILC2 Axis to Promote Allergic Airway Inflammation

Abstract

Small proline-rich proteins (SPRRs), components of cornified cell envelope precursors, have recently been found to participate in airway diseases. However, their role in allergic airway inflammatory conditions remains unknown. Here, we explored the expression of SPRR3 in house dust mite (HDM)-sensitized/challenged mice and attempted to elucidate the regulatory role of SPRR3 in allergic airway inflammation. SPRR3 was identified via bioinformatics analysis of Gene Expression Omnibus (GEO) databases and further confirmed to be upregulated in the lungs of asthmatic mice. Knockdown of SPRR3 via the intratracheal route significantly inhibited eosinophils in bronchoalveolar lavage fluid (BALF) and suppressed the expressions of type 2 cytokines (IL-4, IL-5, and IL-13) in BALF and lung tissues. Further, SPRR3 knockdown reduced the expression of IL-33 and further attenuated the activation of the PI3K/AKT/NF-κB signaling pathway in the recruitment of group 2 innate lymphoid cells (ILC2s) to inhibit allergic airway inflammation. In vitro, SPRR3 siRNA could alleviate HDM-induced inflammatory responses in BEAS-2B cells. This study reveals the regulatory role of SPRR3 in allergic airway inflammation, identifying this protein as a potential novel therapeutic target for asthma.

Interleukin‐33 increases type 2 innate lymphoid cell count and their activation in eosinophilic asthma

“…Accordingly, PI3Kδ reduced the expression of IL‐33 and number of ILC2s, thereby inhibiting the allergic inflammatory response 34 . Leptin, a small proline protein, and LAIR‐1 regulate ILC2s by targeting the PI3K‐AKT pathway, hence affecting the severity of asthma 35–37 . Therefore, we hypothesized that IL‐33 and ILC2s play a role in asthma via the PI3K/AKT signaling pathway.…”

ILC2s expanded by exogenous IL-33 regulate CD45+CD11b+F4/80high macrophage polarization to alleviate hepatic ischemia-reperfusion injury

“…Similar results were reported by Li and Sakai et al (20,21), who found that ST2, the receptor for IL-33, was not expressed by liver resident macrophages, thereby demonstrating that endogenous IL-33 exerts a hepatoprotective effect as a result of increased NF-kB and Bcl-2 expression in hepatocyte and is independent of KCs. However, results from several studies have indicated that IL-33/ILC2s regulate M2 polarization of macrophages (40)(41)(42) and that IL-33 can stimulate ILC2 proliferation (19,43,44), leading to the conclusion that although IL-33 is capable of regulating the polarization of macrophages in vivo, this ability is reliant on ILC2s. Our findings, as described above, suggest that the protective effects of ILC2s in hepatic IRI may rely on exogenous IL-33.…”

“…Exogenous IL-33 is a potent stimulator of ILC2 proliferation (19), and a role for IL-33 in mouse models of hepatic IRI has been previously described. Li Shu et al demonstrated that pretreatment with exogenous IL-33 reduced warm hepatic IRI in mice, and that this protective effect of IL-33 on hepatic IRI was mainly due to a Th1 to Th2 type shift (20).…”

Qizhi Kebitong Formula Ameliorates Streptozocin-Induced Diabetic Osteoporosis through Regulating the PI3K/Akt/NF-κB Pathway

“…Among them, Akt was identified as a unique signaling intermediate in bone homeostasis that controlled the differentiation of osteoblasts and osteoclasts, which was a direct downstream target of PI3K to inhibit the release of inflammatory factors [32][33][34][35][36]. Moreover, NF-κB was also a key downstream factor of the PI3K/Akt pathway, which enhanced the degree of inflammatory response and promoted the differentiation of osteoclast precursors [37,38]. Meanwhile, the PI3K/Akt signaling pathway not only affects inflammatory factors such as NF-κB and TNF-α but also induced the inflammatory reaction in the internal environment of the body.…”