Targeting the p38α pathway in chronic inflammatory diseases: Could activation, not inhibition, be the appropriate therapeutic strategy?

Abstract

Chronic inflammatory diseases (CIDs) afflict millions worldwide and remain incurable. The mitogen-activated protein kinase (MAPK) p38α is a critical node in the intricate acute inflammatory response. It induces the production of various pro-inflammatory mediators, primarily via the MAPK-activated protein kinase 2 (MK2). This, coupled with its sustained activation in CIDs, has led to the assumption that dysregulated pro-inflammatory p38α-dependent pathways are central drivers of chronic inflammation. Inhibiting the p38α cascade thus seems a logical therapeutic strategy, leading to significant efforts towards developing p38α- and MK2-specific inhibitors. However, recent studies raise the possibility that the effects of chronic p38α activation in CIDs have been misinterpreted. In cell cultures and murine models, constitutive p38α activity causes dramatic downregulation, rather than activation, of downstream elements such as MK2, via the ubiquitin-proteasome system, and phospho-Hsp27. Perhaps, sustained p38α activity promotes CIDs by inducing degradation of essential components of the p38α pathway. If this notion is genuine, then the current pharmacological strategy, focused on the inhibition of these components, is counter-productive and may explain why no p38α or MK2 inhibitor has made it to the clinic. It could be that an appropriate strategy should involve restoring or inducing certain p38α targets instead.

Introduction

The number of individuals who suffer from chronic inflammatory diseases (CIDs) is steadily increasing with some diseases reaching epidemic proportions. An estimated 25% of the human population suffers from non-alcoholic fatty liver diseases (NAFLDs) (Younossi et al., 2019). About 300 and 384 million individuals suffer from asthma or chronic obstructive pulmonary disease (COPD) respectively, while the latter is also the 3rd leading cause of global disease mortality (Collaborators, GBD 2015 Chronic Respiratory Disease, 2017). Another irreversible and fatal disease of the lung is idiopathic pulmonary fibrosis (IPF) – which is rarer, but with a median survival of 3–5 years after diagnosis (Hyldgaard, Møller, & Bendstrup, 2020). Rheumatoid arthritis (RA) is estimated to affect ~50 million people worldwide (Caplazi et al., 2015) and inflammatory bowel diseases (IBDs), including Crohn's disease, affect ~6.8 million people globally (Collaborators, GBD 2017 Inflammatory Bowel Disease, 2020). These numbers show that the socioeconomic burden of CIDs is enormous, highlighting the necessity to urgently develop more efficacious therapeutics. Yet, definitive cures for CIDs remain unavailable today.

Unlike infectious diseases and cancers, where pathogens and oncogenic mutations, respectively, are better characterized, the causes of CIDs and their exact aetiology are only partially understood at best. The current dogma suggests that CIDs arise due to a combination of environmental, behavioural and genetic factors. Some CIDs are strongly associated with particular risk factors, e.g. smoking and air pollution for COPD; obesity and a high-fat diet for fatty liver diseases. However, the sequence of events leading from the unknown initial molecular triggers up to the eventual pathology remains vague (Guo et al., 2018; Mannino & Buist, 2007; Tilg, Adolph, & Moschen, 2021; Tilg & Moschen, 2010). Notably, these risk factors only increase the likelihood of developing the disease, but they may not be direct causative agents which trigger the eventual pathology. Individuals exposed to such factors may not develop the associated CID, while others with no significant exposure history could still develop them eventually. For example, cigarette smoke is a well-established risk factor behind COPD, but ‘never-smokers’ are known to account for a significant number of patients (Lamprecht et al., 2011). This overall lack of understanding with regards to the pathogenesis and aetiology of CIDs has hindered the development of therapeutics (Furman et al., 2019; Tabas & Glass, 2013). As of today, steroids and immunosuppressants are the first-line therapeutic options for CIDs. While such therapeutics have proven highly effective in ameliorating the symptoms of inflammation, they are not long-term solutions as they cannot definitively cure CIDs. Steroid resistance is a challenge facing the prolonged use of corticosteroids, while immunosuppression has its obvious negative effects (Hardy, Raza, & Cooper, 2020). Targeted therapy, which is becoming central to cancer treatment (Baudino, 2015), is less common in fighting CIDs, primarily because of the lack of clear understanding regarding their aetiology and causes at the molecular level. Indeed, there are drugs for CIDs which target specific molecules, including the monoclonal antibodies adalimumab, tocilizumab and vedolizumab for TNF-α, IL-6 receptor, and α₄β₇ integrin, respectively (Rubbert-Roth, Furst, Nebesky, Jin, & Berber, 2018; Vena & Cassano, 2007; Wyant, Fedyk, & Abhyankar, 2016), and small molecule inhibitors such as tofacitinib for JAK1 and JAK3, as well as baricitinib for JAK1 and JAK2 (McInnes et al., 2019). However, these act on targets which contribute to the inflammatory state but are not necessarily part of the pathogenic machinery. Another important molecule that has attracted significant efforts in targeted therapies is the mitogen-activated protein kinase (MAPK) p38α (Canovas & Nebreda, 2021). Unfortunately, none of the numerous inhibitors developed for this target have reached the clinic. Recent studies, which are summarised here, may provide an explanation for this insurmountable obstacle and suggest modifications to the current strategy.