Resistin-like molecules

The resistin-like molecules (RELM) α, β and γ and their namesake resistin (RELM family) are secreted proteins. RELM proteins play a role in a variety of diseases, including microbial infections (e.g. bacterial and helminthic infections), inflammatory diseases (e.g. asthma, fibrosis) and metabolic disorders (e.g. diabetes) (Mavi P et al. 2014).

The resistin-like molecules (RELM) exhibit structural and sequential homology, but show considerable diversity in expression and function within their mammalian host. All molecules of the RELM family have a length of 105-114 aa with three domains: (i) an N-terminal signal sequence, (ii) a variable middle portion, and (iii) a highly conserved C-terminal characteristic sequence that makes up almost half of the molecule. The characteristic region of RELMs contains a unique and invariable spacing between the cysteine residues: C-X11-C-X8-C-X-C-X3-C-X10-C-X-C-X-C-X9-CC-X3-6-END. This is reminiscent of the so-called "EGF repeats", which are characteristic of a number of signaling molecules. Presumably, the unique cysteine pattern contributes to the folding and multimerization of RELMs. We hypothesize that the highly conserved characteristic region contributes to binding to a related family of receptors whose existence has yet to be proven. Each RELM likely has distinct biological functions consistent with its unique expression pattern.

RELMs show considerable differences in their distribution and function. Their expression 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 and PI3K/Akt/mTOR signaling pathways.

RELM proteins are involved in a variety of physiological and pathological processes, including inflammatory responses, cell proliferation, glucose metabolism and barrier defense. Communities of resident microorganisms such as pathogenic S. aureus trigger the expression of RELMα when transferred to the germ-free skin of mice.

RELMα and vitamin A/isotretinoin: It has been shown that RELMα and the RELM family member resistin are expressed by keratinocytes and sebocytes. Both proteins have an antimicrobial function. Their expression requires the presence of vitamin A. RELMα is also induced by the vitamin A analog isotretinoin (Harris TA et al. 2019). This could explain why vitamin A analogs are effective in certain skin diseases (Harris TA et al. 2019).

While the expression pattern and molecular regulation of RELM proteins are well characterized, the receptors for RELM proteins are still unclear (Pine GM et al. 2018). One possibility is that RELMα expression is controlled by pattern recognition receptors of the host, such as Toll-like receptors (TLR) expressed on skin epithelial cells. This assumption is supported by the fact that TLR signaling in intestinal epithelial cells controls the expression of several antimicrobial proteins in epithelial cells, including REGIIIγ and RELMβ and β-defensin in the skin. Cathelicidin expression is also indirectly controlled by TLR signaling. A second possible mechanism involves the sensing of bacterial signals by pattern recognition receptors on immune cells that monitor tissue beneath the skin surface, followed by feedback to the epidermis by cytokines. Studies on intestinal REGIIIγ suggest that its expression may be triggered by cytokine signaling between dendritic cells, type 3 innate lymphoid cells (ILC) and intestinal epithelial cells. A third possibility is that skin bacteria induce the expression of the RELM protein via their metabolic products.

RELMα mRNA is most abundant in white adipose tissue. Expression of RELMα was also observed in breast tissue, which contains a considerable fat layer. However, unlike resistin, RELMα was not expressed in 3T3-L1 adipocytes or in preadipocytes, suggesting that RELMα may be produced by the stromal vascular components of adipose tissue. In contrast to resistin, RELMα mRNA is also detectable in the heart, lung and tongue.

RELMβ was detected in the colon of mice, but not in other tissues.

1. Harris TA et al. (2019) Resistin-like Molecule α Provides Vitamin A-Dependent Antimicrobial Protection in the Skin. Cell Host Microbe 25:777-788
2. Mavi P et al. (2014) Allergen-induced resistin-like molecule-α promotes esophageal epithelial cell hyperplasia in eosinophilic esophagitis. Am J Physiol Gastrointest Liver Physiol 307:G499-507.
3. Munitz A et al. (2012) Resistin-like molecule-α regulates IL-13-induced chemokine production but not allergen-induced airway responses. Am J Respir Cell Mol Biol 46:703-713.
4. Nair MG et al. (2009) Alternatively activated macrophage-derived RELM-{alpha} is a negative regulator of type 2 inflammation in the lung. J Exp Med 206:937-952.
5. Pine GM et al. (2018) Here, there and everywhere: Resistin-like molecules in infection, inflammation, and metabolic disorders. Cytokine110:442-451.