The LIM-Only Protein Four and a Half LIM Domain Protein 2 Attenuates Development of Psoriatic Arthritis by Blocking Adam17-Mediated Tumor Necrosis Factor Release

Abstract

Four and a half LIM domain protein 2 (Fhl2) is an intracellular adaptor molecule with a high protein-protein interaction capacity. It acts as a modulator of several signaling molecules in the cytosol and as a cofactor of transcription in the nucleus. Recent studies suggest the role of Fhl2 in tissue repair and the anti-inflammatory response. Herein, we show that Fhl2-deficient mice develop a more severe psoriatic arthritis disease under induction of the inducible human tumor necrosis factor (hTNF) transgene than wild-type mice. The disease was accompanied by increased infiltration of activated macrophages and T regulatory cells in skin and digit joints as well as by increased expression of matrix metalloproteases and bone-specific proteases. The more severe pathogenesis of psoriatic arthritis in Fhl2 knockout mice coincided with enhanced levels of soluble hTNF cytokine, but surprisingly not with transcription of the hTNF transgene. Studying the shedding of cell membrane-bound hTNF by Adam17, a known Fhl2 interacting protein, revealed an enhanced release of TNF in the absence of Fhl2. In summary, our results show that Fhl2 anticipates the emerging inflammation and specifically the development of psoriatic arthritis by impeding the Adam17-mediated release of TNF.

The role of FHL2 in wound healing and inflammation

“…In recombinant human TNF-a-expressing transgenic mice that develop a severe form of rheumatoid arthritis within the first 10 wk after birth (29), FHL2 levels increased during early phases of rheumatoid arthritis development and decreased later on when the disease entered the chronic phase. Here, synovial fibroblasts and chondrocytes showed the highest expression (30,31). Also, during psoriasis and inflammatory bowel disease, FHL2 was significantly down-regulated in later stages of disease progression (30, 32 and unpublished results).…”

“…These facts indicate that FHL2 is up-regulated during active tissue regeneration steps and that the failure of tissue repair and the development of chronic wounds or diseases always accompanies its suppression (9,25,27,30,31). These data further imply that deficiency of FHL2 should impair wound healing and foster development of chronic diseases.…”

“…It is noteworthy that FHL2 might support tumor growth and metastasis, both directly being overexpressed in tumor cells and indirectly when it is overexpressed in tumorassociated stroma cells (2,10,26,85,86). To the contrary, sustained down-regulation of the FHL2 protein supports MMP expression and transition of wounds into chronic forms (30,31,42). FHL2 is involved in different steps of the wound-healing process, supporting tissue repair and coordinating inflammation.…”

“…Furthermore, FHL2-KO mice seem to have a reduced threshold for development of several chronic diseases. It was reported that loss of the LIM-only protein FHL2 encouraged the development of corneal angiogenesis, hypertrophic cardiomyopathy (38), osteopenia (37), fibrosis (25,39,40), arthritis (30,31), psoriasis (30), and gliosis in the adult brain (41).…”

“…Interestingly, although FHL2 supports the induction of proinflammatory cytokines like TNF-a, IL-6, or IL-8 (33,52,53,55), it represses the transcription of the anti-inflammatory cytokine TGF-b (33,56) and inhibits the activity of sphingosine kinase 1 and, thereby, the anti-inflammatory acting sphingosine-1-phosphate (S1P)-mediated signaling axis (57). Alternatively, proinflammatory cytokines like IL-1b, IL-6, and TNF-a down-regulate FHL2 expression (30,31,42), but antiinflammatory agents TGF-b and S1P are the most effective FHL2 inducers (26,31,(58)(59)(60). Thus, the relationship between FHL2 and pro-and anti-inflammatory cytokines appears to be complex.…”