Resistin-like molecules: a marker, mediator and therapeutic target for multiple diseases

Abstract

Resistin-like molecules (RELMs) are highly cysteine-rich proteins, including RELMα, RELMβ, Resistin, and RELMγ. However, RELMs exhibit significant differences in structure, distribution, and function. The expression of RELMs is regulated by various signaling molecules, such as IL-4, IL-13, and their receptors. In addition, RELMs can mediate numerous signaling pathways, including HMGB1/RAGE, IL-4/IL-4Rα, PI3K/Akt/mTOR signaling pathways, and so on. RELMs proteins are involved in wide range of physiological and pathological processes, including inflammatory response, cell proliferation, glucose metabolism, barrier defense, etc., and participate in the progression of numerous diseases such as lung diseases, intestinal diseases, cardiovascular diseases, and cancers. Meanwhile, RELMs can serve as biomarkers, risk predictors, and therapeutic targets for these diseases. An in-depth understanding of the role of RELMs may provide novel targets or strategies for the treatment and prevention of related diseases. Video abstract.

Keywords: Inflammation; Lung disease; Parasite; Proliferation; Resistin-like molecules.

Fig. 1

Signaling pathways of RELMα and RELMβ inducing the inflammation in the lung and colon. RELMα promotes IL-6 expression in macrophages in a HIF-1α-dependent manner. RELMα induces a series of inflammatory cytokines and chemokines such as interleukin IL-1β, -1ra, -16 and -17; CXCL-1, -2, -9, -10, -13; MCP-1; M-CSF; TIMP-1; and TREM-1 in BALF. RELMα induces acetylation of HMGB1 by inhibiting deacetylase Sirt 1, thereby enhancing vascular inflammation. RELMα promotes the release of inflammatory cytokines such as serum IL-1β, IL-6, IL-8, TNF-α, and CRP. M2 macrophage-derived RELMα binding to CD4⁺ T cells can attenuate lung inflammatory response by decreasing the production of Th2 cytokines (IL-4, IL-5, and IL-13) derived from CD4⁺ T cells in a BTK-dependent manner. Lung B cells can produce RELMα to downregulate IL-17A of γδ T cells, thereby limiting emphysema. RELMα exacerbates intestinal inflammation by promoting the IL-23p19/IL-17A immune axis. Eosinophils-derived RELMα promotes BMD macrophage activation by synergizing with LPS to amplify LPS-induced proinflammatory cytokine (IL-6 and TNF-α) secretion and suppresses anti-inflammatory cytokines (IL-10) production. RELMα induces proinflammatory eosinophil-directed cytokines (such as IL-5, CCL11, and CCL5) and IL-17. Goblet cell-derived RELMβ stimulates TNF-α, IL-6, and CCL5 in macrophages, thereby promoting intestinal inflammation. RELMβ-exposed macrophages induce expression of MHC II and secretion of IL-12/23p40, which can increase IFN-γ production by effector Th1 cells recruited to areas of inflammation

Fig. 2

Signaling pathways of RELMα and RELMβ promoting PAH in the lung. RELMα facilitates vascular remodeling through IL-4/IL-4Rα signaling pathway to accelerate PMVECs proliferation, VEGF expression, and MCP-1 production. In PAH, HMGB1, which is produced and released by RELMα-stimulated ECs, leads to induction of autophagy and inhibition of apoptosis and BMPR2 expression in PVSMCs, thus reducing PVSMCs proliferation. ECs-derived HMGB1 also activates RAGE in ECs and PVSMCs to form a positive feedback loop, which contributes to the secretion and release of more HMGB1 and increases the expression of RAGE in these pulmonary vascular cells. RELMα induces robust proliferation of MSCs dependent on PI3K/Akt and ERK1/2 activation. RELMβ triggers PASMCs proliferation and pulmonary artery remodeling, resulting in PAH at least partially through Ca²⁺-dependent PI3K/Akt/mTOR pathway and protein kinase C (PKC)/MAPK pathway. RELMβ leads to PLC-mediated inhibition of KCNK3, thereby promoting PASMCs proliferation during PAH development. RELMβ promotes the proliferation of human PASMCs via the FAK-survivin pathway. In BECs, RELMβ increases cells proliferation through phosphorylation of ERK1/2, PI3K and Akt, and elevates the expression of a range of remodeling mediators, including TGF-β2, EGF, VEGF, and MUC5AC, which contribute to airway remodeling. RELMβ increases the production of TGF-β1, TGF-β2, collagen I, fibronectin, α-SMA, laminin α1, and Hapl1 as well as the proliferation of human lung fibroblasts, which have an important functional role in airway remodeling. TGF-β1 can trigger RELMβ transcription to promote EndMT, proliferation, and migration in human UVECs and human PAECs by activation of SMAD2/3/4

Fig. 3

RELMα and RELMβ participate in various diseases