Cigarette smoke aggravates asthma by inducing memory-like type 3 innate lymphoid cells

Abstract

Although cigarette smoking is known to exacerbate asthma, only a few clinical asthma studies have been conducted involving smokers. Here we show, by comparing paired sputum and blood samples from smoking and non-smoking patients with asthma, that smoking associates with significantly higher frequencies of pro-inflammatory, natural-cytotoxicity-receptor-non-expressing type 3 innate lymphoid cells (ILC3) in the sputum and memory-like, CD45RO-expressing ILC3s in the blood. These ILC3 frequencies positively correlate with circulating neutrophil counts and M1 alveolar macrophage frequencies, which are known to increase in uncontrolled severe asthma, yet do not correlate with circulating eosinophil frequencies that characterize allergic asthma. In vitro exposure of ILCs to cigarette smoke extract induces expression of the memory marker CD45RO in ILC3s. Cigarette smoke extract also impairs the barrier function of airway epithelial cells and increases their production of IL-1β, which is a known activating factor for ILC3s. Thus, our study suggests that cigarette smoking increases local and circulating frequencies of activated ILC3 cells, plays a role in their activation, thereby aggravating non-allergic inflammation and the severity of asthma.

Memory-like innate lymphoid cells in the pathogenesis of asthma

“…Besides, CD45RO expressing ILC2s showed more potential to produce type 2 cytokines (79). Moreover, the possibility of memory ILCs is further supported by Ham et al, which showed that the CD45RO expressing ILC3s are elevated in smoking asthma patients and that the CD45RO + ILC3 frequencies correlated positively with disease severity (9). Thus, memory ILCs may be involved in asthma pathogenesis and may help explain why asthma associates with diverse antigens and presents as different endotypes (allergic and non-allergic) and phenotypes (e.g., infectioninduced asthma exacerbations in children, obesity-induced asthma, and steroid-resistant asthma) (Figure 3).…”

“…Besides, CD45RO expressing ILC2s showed more potential to produce type 2 cytokines ( 79 ). Moreover, the possibility of memory ILCs is further supported by Ham et al., which showed that the CD45RO expressing ILC3s are elevated in smoking asthma patients and that the CD45RO + ILC3 frequencies correlated positively with disease severity ( 9 ).…”

“…memory-like CD45RO + ILC3s increased in smoker asthmatics blood. CD45RO + circulating ILC3s were associated with the asthmatic severity and counts of the peripheral blood neutrophils ( 9 ). Below, we discuss the current understanding of innate immune memory, memory-like ILCs, and the potential roles of ILC memory in asthma.…”

“…The possibility that ILCs contribute to asthma is supported by many studies showing ILC2 frequencies are elevated in the periphery and lung of asthmatics ( 8 ). Moreover, there is growing evidence that ILC1 and ILC3 cells also participate in different asthma phenotypes, such as neutrophil-dominated asthma ( 9 ). In addition, murine models of acute onset and chronic asthma clearly show that ILCs are involved in various stages of asthma ( 10 ).…”

Special Issue on ‘Asthma and Allergic Inflammation’

“…Similar to eosinophilic asthma, neutrophilic disease is also dependent on the synergistic cooperation between innate and adaptive immune mechanisms. In fact, both Th17 lymphocytes and group 3 of innate lymphoid cells (ILC3) produce IL-17A and IL-17F, which in turn stimulate immune inflammatory cells (monocytes/macrophages) and resident structural cells (airway epithelial cells and subepithelial fibroblasts) to release powerful neutrophil chemoattractant mediators such as IL-8 (CXCL8) [ 13 ]. Other cellular interactions involving innate and adaptive immune responses refer to the bioactivities of Th1 lymphocytes and group 1 of innate lymphoid cells (ILC1), releasing interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), which contribute to the inflammation of the neutrophilic airway [ 14 ].…”