Oral administration of the selective GPR120/FFA4 agonist compound A is not effective in alleviating tissue inflammation in mouse models of prototypical autoimmune diseases

Abstract

Abstractω3‐polyunsaturated free fatty acids (ω3‐PUFAs), particularly docosahexaenoic (DHA) and eicosapentaenoic acid (EPA), are thought to exert health promoting effects in metabolic and in inflammatory diseases. The molecular mechanisms of these beneficial effects are only partially understood. DHA and EPA activate Free Fatty Acid receptor 4 (GPR120/FFA4). Recently, the first orally available, synthetic ligand of FFA4, 3‐[2‐chloro‐5‐(trifluoromethoxy)phenyl]‐3‐azaspiro[5.5]undecane‐9‐acetic acid (“compound A”; cpd A) has been developed. Cpd A exhibits distinctly higher potency, efficiency, and selectivity at FFA4 than ω3‐PUFAs and ameliorates insulin resistance and adipose tissue inflammation in the mouse. With GPR120/FFA4 activation believed to also attenuate tissue inflammation in autoimmune diseases, cpd A may also have a beneficial effect in these diseases. We have therefore addressed the therapeutic potential of cpd A in mouse models of three prototypical autoimmune diseases, specifically psoriasis, rheumatoid arthritis, and bullous pemphigoid. The effect of cpd A on the course of Aldara™‐induced psoriasis‐like dermatitis, K/BxN serum transfer arthritis, and antibody transfer pemphigoid disease‐like dermatitis was scrutinized. Cpd A did not alter the course of Aldara‐induced psoriasis‐like dermatitis, K/BxN serum transfer arthritis, or antibody transfer pemphigoid disease‐like dermatitis. Our results suggest that therapeutic regimens solely relying on FFA4 activation do not bear the potential to treat inflammatory diseases. With cpd A distinctly more potent in activating GPR120/FFA4 than ω3‐PUFAs, this also suggests that GPR120/FFA4 activation by ω3‐PUFAs does not significantly contribute to the health‐promoting effects of ω3‐PUFAs in autoimmune diseases.

Free fatty acid receptor 4 (FFA4) activation ameliorates 2,4-dinitrochlorobenzene-induced atopic dermatitis by increasing regulatory T cells in mice

“…On the other hand, Wannick et al reported that oral administration of 50 mg/kg compound A was not effective in alleviating tissue inflammation in mouse models of autoimmune diseases, specifically imiquimod-induced psoriasis-like dermatitis, K/BxN serum transfer arthritis, and antibody transfer pemphigoid disease-like dermatitis; the dosage of compound A used in this study was even higher than that used in our study (30 mg/kg) [ 33 ]. There are three different factors to consider when comparing the two studies.…”

“…Because compound A was effective against insulin resistance and adipose tissue inflammation in C57BL6 mice when administered orally [ 15 ], two factors could not explain the negative outcomes of the autoimmune disease models used by Wannick et al Further investigation is necessary to elucidate why compound A was not effective against autoimmune diseases. Wannick et al suggested that FFA4 activation does not significantly contribute to the health-promoting effects of omega-3 polyunsaturated fatty acids in autoimmune diseases [ 33 ]. This possibility could be partly supported by the specialized proresolving mediators of DHA and EPA derivatives, such as resolvin D1, resolvin D2, resolvin E, protectin D1, and maresin 1 [ 34 ].…”

The G Protein-Coupled Receptor (GPR) 15 Counteracts Antibody-Mediated Skin Inflammation

“…Purified anti-Col7 IgG were filter-sterilized (pore size 0.2 μm), quantified by NanoDrop (Thermo Fischer Scientific GmbH, Dreieich, Germany), and assessed for their reactivity to murine Col7 by indirect immunofluorescence analysis performed on murine tail skin sections as previously described ( 21 ). Antibody transfer BP-like EBA was induced, as previously described ( 12 , 21 ). Briefly, mice were injected s.c. with 50 μg of affinity purified anti-Col7 IgG on days 0, 2, and 4 of the experiment.…”

Long Chain Fatty Acids as Modulators of Immune Cells Function: Contribution of FFA1 and FFA4 Receptors

“…However, other studies have suggested that therapies based only on FFA4 receptor activation would not be helpful in the treatment of inflammatory diseases. They observed that Compound A did not modify the course of Aldara-induced psoriasis-like dermatitis, K/BxN serum transfer arthritis, or antibody transfer pemphigoid disease-like dermatitis (Wannick et al, 2018 ). Metabolex 36 and metabolex compound B have been used as FFA4 receptor agonists.…”