Retnla Overexpression Attenuates Allergic Inflammation of the Airway

Abstract

Resistin-like molecule alpha (Retnla), also known as ‘Found in inflammatory zone 1’, is a secreted protein that has been found in bronchoalveolar lavage (BAL) fluid of ovalbumin (OVA)-induced asthmatic mice and plays a role as a regulator of T helper (Th)2-driven inflammation. However, the role of Retnla in the progress of Th2-driven airway inflammation is not yet clear. To better understand the function of Retnla in Th2-driven airway inflammation, we generated Retnla-overexpressing (Retnla-Tg) mice. Retnla-Tg mice showed increased expression of Retnla protein in BAL fluid and airway epithelial cells. Retnla overexpression itself did not induce any alteration in lung histology or lung function compared to non-Tg controls. However, OVA-sensitized/challenged Retnla-Tg mice had decreased numbers of cells in BAL and inflammatory cells accumulating in the lung. They also showed a reduction in mucus production in the airway epithelium, concomitant with a decreased Muc5ac level. These results were accompanied by reduced levels of Th2 cytokines, including interleukin (IL)-4, IL-5, and IL-13, with no effect on levels of OVA-specific immunoglobulin isotypes. Furthermore, phosphorylation of ERK was markedly reduced in the lungs of OVA-challenged Retnla-Tg mice. Taken together, these results indicates that Retnla protects against Th2-mediated inflammation in an experimental mouse model of asthma, suggesting that therapeutic approaches to enhance the production of Retnla or Retnla-like molecules could be valuable for preventing allergic lung inflammation.

Nicotinic alpha 7 receptor expression and modulation of the lung epithelial response to lipopolysaccharide

“…This included 152 genes expressed preferentially in the α7 G samples and 210 in the α7 E260A:G (Table 2 (see S1 Table) and Fig 5A). Some examples of the genes that were reduced in constitutive expression in the α7 E260A:G include Postn (periostin), whose gene product imparts cell adhesion and extracellular matrix remodeling [50], Retnla (resistin-like alpha), which impacts on IL-6 secretion and allergic inflammatory responses [51,52], Cyp2a5 (cytochrome P450 family 2 subfamily a5) that modulates the LPS response and has been suggested to degrade nicotine [53], and Ltf (lactotransferrin) which participates in antimicrobial activity [54,55]. Also, a recurring gene that is suppressed in the α7 E260A:G is Lcn2 (lipocalin2), which can also contribute to modulating the host defenses to multiple bacterial species [54,55].…”

“…Also altered are multiple genes associated with ATII cells including the surfactant family genes Sftpa1, Sftpb and Sftpc. Other transcripts of interest include IL-33 that in mice is involved in host defense and wound repair [59], Hc (hemolytic complement) that contributes to the inflammatory response in allergic lung disease and Retnla (resistin-like alpha) that is also a contributor to attenuating allergic inflammatory responses [52]. The ATII cells exhibit expression variance that is most notable in the horizontal axis which is consistent with the strong tendency of the gene expression in these cells to be scaled in the direction of α7 G expression exceeding α7 E260A:G under constitutive conditions, but exhibiting a strong reversal of this relative α7-gentoyte expression difference in response to i.n.…”

Non-traditional cytokines: How catecholamines and adipokines influence macrophages in immunity, metabolism and the central nervous system

“…Conversely, RELMα −/− mice exhibited reduced bleomycin-induced fibrosis. In contrast, transgenic mice that overexpressed RELMα were protected from ova-induced allergic inflammation and exhibited reduced Th2 cytokines [81]. These studies suggest that the immune function of RELMα is complex and may depend on which cell-type expresses RELMα, the RELMα levels and the type of inflammatory environment.…”

Hematopoietic cell-derived RELMα regulates hookworm immunity through effects on macrophages

“…In mouse models of asthma, RELMα expression is elevated in the lung following allergen challenge, where it was postulated to promote airway hyperresponsiveness . Other studies using genetic deletion of RELMα or RELMα overexpression have suggested instead a beneficial function for RELMα in limiting Th2 cytokine‐induced inflammation in mouse models of asthma and mouse helminth infection . Although protective in dampening lung inflammatory responses, RELMα paradoxically impaired optimal parasite expulsion in infection with the hookworm Nippostrongylus brasiliensis ( Nb ) …”