Phosphodiesterase-4 (PDE4), mainly present in immune cells, epithelial cells, and brain cells, manifests as an intracellular non-receptor enzyme that modulates inflammation and epithelial integrity. Inhibition of PDE4 is predicted to have diverse effects via the elevation of the level of cyclic adenosine monophosphate (cAMP) and the subsequent regulation of a wide array of genes and proteins. It has been identified that PDE4 is a promising therapeutic target for the treatment of diverse pulmonary, dermatological, and severe neurological diseases. Over the past decades, numerous PDE4 inhibitors have been designed and synthesized, among which roflumilast, apremilast, and crisaborole were approved for the treatment of inflammatory airway diseases, psoriatic arthritis, and atopic dermatitis, respectively. It is regrettable that the dramatic efficacies of a drug are often accompanied by adverse effects, such as nausea, emesis, and gastrointestinal reactions. However, substantial advances have been made to mitigate the adverse effects and obtain better benefit-to-risk ratio. This review highlights the dialectical role of PDE4 in drug discovery and the disquisitive details of certain PDE4 inhibitors to provide an overview of the topics that still need to be addressed in the future.

Ulcerative colitis (UC) is a chronic, nonspecific inflammatory bowel disease (IBD) characterized by complicated and relapsing inflammation in the gastrointestinal tract. SM934 is a water-soluble artemisinin analogue that shows anti-inflammatory and immuno-regulatory effects. In this study, we investigated the effects of SM934 on UC both in vivo and in vitro. A mouse model of colitis was established in mice by oral administration of 5% dextran sulfate sodium (DSS). SM934 (3, 10 mg/kg per day, ig) was administered to the mice for 10 days. After the mice were sacrificed, colons, spleens and mesenteric lymph nodes (MLNs) were collected for analyses. We showed that SM934 administration restored DSS-induced body weight loss, colon shortening, injury and inflammation scores. Furthermore, SM934 administration significantly decreased the disease activity index (DAI), histopathological scores, and myeloperoxidase (MPO) activities in colonic tissues. Moreover, SM934 administration dose-dependently decreased the mRNA and protein levels of DSS-induced pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α), and the percentage of macrophages and neutrophils in colon tissues. The effects of SM934 on LPS-stimulated RAW 264.7 cells and THP-1-derived macrophages were examined in vitro. Treatment with SM934 (0.8, 8, 80 μmol/L) dose-dependently decreased the production of pro-inflammatory mediators in LPS-stimulated RAW264.7 cells and THP-1-derived macrophages via inhibiting activation of the NF-κB signaling. Our results reveal the protective effects of SM934 on DSS-induced colitis can be attributed to its suppressing effects on neutrophils and macrophages and its inhibitory role in the NF-κB signaling, suggests that SM934 might be a potential effective drug for ulcerative colitis.

Colony-stimulating factor-1 receptor (CSF-1R), also known as FMS kinase, is a type I single transmembrane protein mainly expressed in myeloid cells, such as monocytes, macrophages, glial cells, and osteoclasts. The endogenous ligands, colony-stimulating factor-1 (CSF-1) and Interleukin-34 (IL-34), activate CSF-1R and downstream signaling pathways including PI3K-AKT, JAK-STATs, and MAPKs, and modulate the proliferation, differentiation, migration, and activation of target immune cells. Over the past decades, the promising therapeutic potential of CSF-1R signaling inhibition has been widely studied for decreasing immune suppression and escape in tumors, owing to depletion and reprogramming of tumor-associated macrophages. In addition, the excessive activation of CSF-1R in inflammatory diseases is consecutively uncovered in recent years, which may result in inflammation in bone, kidney, lung, liver and central nervous system. Agents against CSF-1R signaling have been increasingly investigated in preclinical or clinical studies for inflammatory diseases treatment. However, the pathological mechanism of CSF-1R in inflammation is indistinct and whether CSF-1R signaling can be identified as biomarkers remains controversial. With the background information aforementioned, this review focus on the dialectical roles of CSF-1R and its ligands in regulating innate immune cells and highlights various therapeutic implications of blocking CSF-1R signaling in inflammatory diseases.

Background and Purpose: Ulcerative colitis (UC) is an aetiologically refractory inflammatory disease, accompanied by dysfunction of the epithelial barrier and intestinal inflammation. Phosphodiesterase‐4 (PDE4) serves as an intracellular proinflammatory enzyme, hydrolyzing and inactivating cAMP. Though PDE4 inhibitors have been approved for pulmonary and dermatological diseases, the role of PDE4 inhibition in modulating mucosal immunity in the intestine remains ill‐defined. This study was designed to explore whether PDE4 inhibition by apremilast exerts protective effects in dextran sulfate sodium‐induced murine UC.Experimental Approach: Intestinal inflammation and disease severity were evaluated by morphological, histopathological and biochemical assays, and in vivo imaging. Expression of inflammatory mediators, components of PDE4‐mediated pathways in colon and macrophages were determined using quantitative real‐time PCR, ELISA, Luminex assay, immunostaining, or western blotting, along with siRNA knockdown. Immune cells in mesenteric lymph nodes and colonic lamina propria were analysed by flow cytometry.Key Results: Apremilast attenuated clinical features of UC, suppressing microscopic colon damage, production of inflammatory mediators, oxidative stresses, and fibrosis. Apremilast also promoted epithelial barrier function and inhibited infiltration of immune cells into inflamed tissues, through decreasing expression of chemokines and chemokine receptors. Furthermore, in UC, PDE4A, PDE4B, and PDE4D were highly expressed in colon. Apremilast not only inhibited PDE4 isoform expression but also activated PKA–CREB and Epac‐Rap1 pathways and subsequently suppressed MAPK, NF‐κB, PI3K–mTOR, and JAK–STAT–SOCS3 activation.Conclusion and Implications: Inhibition of PDE4 by apremilast protected against UC, by interfering with mucosal immunity. These findings represent a promising strategy for regulating intestinal inflammation.