Cell type-specific targeting dissociates the therapeutic from the adverse effects of protein kinase inhibition in allergic skin disease

Abstract

The kinase p38α, originally identified because of its endotoxinand cytokine-inducible activity and affinity for antiinflammatory compounds, has been posited as a promising therapeutic target for various immune-mediated disorders. In clinical trials, however, p38α inhibitors produced adverse skin reactions and other toxic effects that often outweighed their benefits. Such toxicity may arise from a perturbation of physiological functions unrelated to or even protective against the disease being treated. Here, we show that the effect of interfering with p38α signaling can be therapeutic or adverse depending on the targeted cell type. Using a panel of mutant mice devoid of p38α in distinct cell types and an experimental model of allergic skin disease, we find that dendritic cell (DC)-intrinsic p38α function is crucial for both antigen-specific T-cell priming and T-cell-mediated skin inflammation, two independent processes essential for the immunopathogenesis. By contrast, p38α in other cell types serves to prevent excessive inflammation or maintain naïve T-cell pools in the peripheral lymphoid tissues. These findings highlight a dilemma in the clinical use of p38α inhibitors, yet also suggest cell-selective targeting as a potential solution for improving their therapeutic index.allergic contact dermatitis | contact hypersensitivity | hapten T he kinase p38α, the most abundant and ubiquitously expressed p38 MAP kinase isoform in mammals, was discovered based on its binding affinity for antiinflammatory compounds (1). The nature of the stimuli that elicited p38α activation and enabled its identification-proinflammatory cytokines, microbial products, and injurious environmental insultsalso hinted at a role for p38α in the immune and stress response (2-4). Pharmacological inhibition of p38α has since held promise for the treatment of allergic, autoimmune, and other diseases of inflammatory etiology. A series of recent clinical studies, however, revealed the frequent occurrence of adverse events, ranging from skin rashes to liver damage, after the use of p38α inhibitors (5-7). These toxicities limited the dose and frequency of p38α inhibitor treatment and have become a liability to fulfilling its promise as an effective therapeutic strategy.The therapeutic index is a relative measure of the efficacy versus toxicity of a treatment regimen. Toxic side effects have often been the cause of the failure of an otherwise effective therapeutic agent such as p38α inhibitors. We questioned whether the adverse effects of p38α inhibitors arose from interference with a physiological function of the protein kinase and, if so, whether the therapeutic and the adverse effects of p38α inhibition were based on distinct cell type-specific mechanisms. In this study, we used a mouse model of allergic contact dermatitis to examine the disease responses of conditional p38α knockout (KO) mice. In these mice, ablation of p38α expression was targeted to keratinocytes, myeloid cells, dendritic cells, or T cells, which represented a simulation of p38...

The Emerging Role of p38 Mitogen-Activated Protein Kinase in Multiple Sclerosis and Its Models

“…Importantly, despite the diversity of cell types where p38 MAPK plays a role, its effects in all of the cell types studied to date in EAE are unidirectionally propathogenic. This is in contrast to other immune-mediated models of inflammation, where emerging evidence points to potential anti-inflammatory roles for this kinase (62)(63)(64), which may explain the lack of efficacy of p38 MAPK inhibitors in treating rheumatoid arthritis (RA) and Crohn's disease (see below).…”

Keratinocyte p38δ loss inhibits Ras-induced tumor formation, while systemic p38δ loss enhances skin inflammation in the early phase of chemical carcinogenesis in mouse skin

“…Nevertheless, the involvement of the non‐epithelial cell‐derived p38δ in skin tumorigenesis cannot be excluded, since p38δ is expressed in many cell types, including immune, endothelial, and mesenchymal cells (reviewed in ), interplay of which with epithelial cells is known to be of key importance for tumor development and progression . Importantly, studies targeting p38α isoform in distinct cell types have revealed cell type‐specific effects of p38α loss on inflammatory and allergic responses in skin, and on inflammatory bowel disease . The effects of keratinocyte‐specific and myeloid cell‐specific p38δ loss on distinct stages of chemical skin carcinogenesis are under investigation in our laboratory.…”

Anti-inflammatory roles of p38α MAPK in macrophages are context dependent and require IL-10

“…Moreover, CKO studies have shown that deletion of p38a in different cell types can have opposing effects on inflammation and disease outcome [17,[19][20][21]. In fact, deletion of p38a in macrophages/ myeloid cells aggravated skin inflammation [17,20] and experimental arthritis [18]. Moreover, we have shown in a mouse model of MS, an autoimmune inflammatory disease of the CNS-that deletion of p38a in myeloid cells can either exacerbate or ameliorate disease in a sex-specific fashion [22].…”

“…Taken together, these results suggest that cell-specific targeting of p38a in myeloid cells may have therapeutic potential in treating colitis and possibly other inflammatory diseases, particularly if combined with restoration of IL-10 levels. In contrast, deletion of p38a in myeloid cells can aggravate skin inflammation [17,20], experimental arthritis [18], and autoimmune CNS inflammation [22], suggesting that perhaps protective functions of myeloid p38a are colitis specific. This notion is supported by the exquisite sensitivity of colitis to the absence of IL-10 and the critical requirement for IL-10 to maintain normal intestinal homeostasis [50,53,54].…”

“…Emerging studies describe a noncanonical role for p38a in dampening, rather than promoting inflammation, potentially via induction of autoinhibitory-feedback mechanisms involving dualspecificity phosphatase 1 and/or immune-suppressive cytokines, such as IL-10 [15][16][17][18], although the functional contribution of these pathways has not been formally demonstrated. Moreover, CKO studies have shown that deletion of p38a in different cell types can have opposing effects on inflammation and disease outcome [17,[19][20][21]. In fact, deletion of p38a in macrophages/ myeloid cells aggravated skin inflammation [17,20] and experimental arthritis [18].…”