An Autophagy Modulator Peptide Prevents Lung Function Decrease and Corrects Established Inflammation in Murine Models of Airway Allergy

Abstract

The involvement of autophagy and its dysfunction in asthma is still poorly documented. By using a murine model of chronic house dust mite (HDM)-induced airway inflammation, we tested the expression of several autophagy markers in the lung and spleen of asthma-like animals. Compared to control mice, in HDM-sensitized and challenged mice, the expression of sequestosome-1/p62, a multifunctional adaptor protein that plays an important role in the autophagy machinery, was raised in the splenocytes. In contrast, its expression was decreased in the neutrophils recovered from the bronchoalveolar fluid, indicating that autophagy was independently regulated in these two compartments. In a strategy of drug repositioning, we treated allergen-sensitized mice with the therapeutic peptide P140 known to target chaperone-mediated autophagy. A single intravenous administration of P140 in these mice resulted in a significant reduction in airway resistance and elastance, and a reduction in the number of neutrophils and eosinophils present in the bronchoalveolar fluid. It corrected the autophagic alteration without showing any suppressive effect in the production of IgG1 and IgE. Collectively, these findings show that autophagy processes are altered in allergic airway inflammation. This cellular pathway may represent a potential therapeutic target for treating selected patients with asthma.

Autophagy-Lysosomal Pathway as Potential Therapeutic Target in Parkinson’s Disease

“…Autophagy is a very dynamic compartmentalized process; it can be increased in certain organs and tissues but decreased in other organs in the same subject. This differential activation has been described in several models of chronic inflammation and autoimmune diseases, for example in murine models of Sjögren’s syndrome [ 303 ], chronic inflammatory demyelinating polyneuropathy [ 304 ] and chronic house dust mite-induced airway inflammation [ 305 ]. With regard to neurons, as indicated above, autophagy is even more complex, with specific stages of the pathway occurring in distinct subcellular compartments.…”

“…As a consequence, treating an individual with a compound to induce or inhibit autophagy can have a range of individual effects. Due to this variety of effects, treating a subject with an inhibitor can restore abnormally weak levels of autophagic activity in another tissue, as illustrated by the effect of the CMA-modulator peptide P140 [ 303 , 304 , 305 ]. P140 that targets CMA and probably indirectly macroautophagy, has shown correcting effect on altered CMA activity, but display no effect on the basal, well balanced and vital autophagy process.…”

The Role of Autophagy in the Function of CD4+ T Cells and the Development of Chronic Inflammatory Diseases

“…In the HDM-induced mouse model, the administration of chloroquine alleviated airway inflammation and improved airway stenosis ( McAlinden et al, 2019 ). The intravenous injection of P140, a downregulator of CMA, attenuated ovalbumin-induced eosinophilic inflammation ( Daubeuf et al, 2021 ).…”

“…Th2 cells section, upregulated Th2 differentiation was observed in autophagy-deficient mice ( Kabat et al, 2016 ). However, two studies have showed that autophagy deficiency in ovalbumin- or HDM-induced inflammation results in reduced eosinophilic inflammation ( McAlinden et al, 2019 ; Daubeuf et al, 2021 ). The results of these two studies are the opposite of those expected by Kabat et al Thus, because these two studies used whole-body autophagy-knockout mice, the specific effect of autophagy on CD4 + T cells in asthma development cannot be fully understood.…”

CIDP: Current Treatments and Identification of Targets for Future Specific Therapeutic Intervention

“…Interestingly, a peptide known as P140, which is issued from the ribonucleoprotein U1-70K, also decreases expression of MHC-II molecules expressed at the surface of mouse and human B cell APCs in lupus [101][102][103][104][105]. P140 has been shown to be efficient in lupus (both in lupus-prone mice and lupus patients [106,107]) as well as in various murine models of inflammation, including primary and secondary Sjögren's syndrome [104,108], chronic house dust mite-induced airway inflammation [109], and CIDP [83]. In the same way as Quinpramine, the P140 mechanism of action involves reducing the hyperactivation of autoreactive T-cells via its effect on MHC-self peptide presentation to the receptor of autoreactive T cells.…”