Therapeutic Targeting Steroid Resistant Pro-Inflammatory NK and NKT-Like Cells in Chronic Inflammatory Lung Disease

Abstract

The innate immune system drives the initiation of inflammation and progression to chronic inflammation in two important chronic inflammatory lung diseases involving the small airways, chronic obstructive pulmonary disease (COPD) and bronchiolitis obliterans syndrome (BOS), following lung transplantation. Recently natural killer T cell like (NKT-like) cells, which represent a bridge between the innate and adaptive immune response as well as the innate natural killer cell (NK) cells, have been shown to be important cells in these two chronic lung diseases. Importantly these cells have been shown to be resistant to commonly used anti-inflammatory drugs such as glucocorticoids and as such their inflammatory nature has been difficult to suppress. Mechanisms leading to steroid resistance in both diseases has recently been shown. Glucocorticoids switch off inflammatory genes by first entering the cell and binding to glucocorticoid receptors (GCRs). The steroid-GCR complex must then be chaperoned into the nucleus via several heat shock proteins, where they engage histone deacetylase 2 to switch off pro-inflammatory gene transcription. Many of these mechanisms are altered in NK and NKT-like cells in COPD and BOS requiring novel intervention using combinations of currently available drugs. Evidence will be presented to show how these drugs can overcome these mechanisms of drug resistance ex vivo advising novel therapeutic strategies for the treatment these two important chronic inflammatory lung diseases.

In utero Exposure to Maternal Chronic Inflammation Transfers a Pro-Inflammatory Profile to Generation F2 via Sex-Specific Mechanisms

“…Previous studies demonstrated an increase in CD28 null NKT lymphocytes in chronic obstructive pulmonary disease, with reduced GR expression. The lack of CD28 costimulatory molecule on lymphocytes is linked to lymphocyte senescence and associated with a further increase in their proinflammatory/cytotoxic (TNF-α, IFN-γ, granzyme, and perforin production) phenotype and glucocorticoid resistance (39,40). In systemic lupus erythematosus, similar results are observed in monocytes, with loss of GR on monocytes being the hallmark of steroid resistance, which is also associated with an increased pro-inflammatory cytokine profile (41).…”

Defective FAS-Mediated Apoptosis and Immune Dysregulation in Gaucher Disease

“…[43] CD8+NKT-like cells are especially noted as key players in the progression of chronic obstructive pulmonary disease and bronchiolitis obliterans and in conferring resistance to glucocorticoids. [44] We do not have the data to connect the decrease of CD8+NKT-like cells to sphingolipid dysfunction due to GBA deficiency and/or to lymphocyte apoptosis defect; therefore, this finding needs to be further investigated with specific studies.…”

Abnormal expression of CD96 on natural killer cell in peripheral blood of patients with chronic obstructive pulmonary disease

“… 20 It has been widely reported that long‐term cigarette smoke exposure, which eventually alters the function of the lung barrier and reduces immune defense mechanisms, is the major cause of COPD. 21 The cytotoxic attacks of NK cell are immediate, do not require prior antigen‐priming, and are instead orchestrated uniquely by myriad receptors with activating or inhibitory functions. 4 In our study, the frequencies of CD16 + NK cells were high in both patients and healthy donors although the frequency was slightly higher in the patient group.…”