Targeting Neutrophils in Severe Asthma via Siglec-9

Abstract

Severe asthma comprises only 5% of patients with asthma, but the burden it brings to the social health system accounts for more than half of all asthmatics. Clinical evidence shows that severe asthma is often linked to the recruitment and activation of neutrophils in the airways. However, the underlying molecular and immunological mechanisms of neutrophilia in severe asthma are not clear and currently available drugs exert only limited effects on neutrophilic inflammation. Great efforts are underway to address the mystery of neutrophilic inflammation in chronic respiratory disorders. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are members of the immunoglobulin gene family. Of note, Siglec-9 is uniquely expressed by human neutrophils and monocytes, as well as a minor population of natural killer cells. Engaging this structure with antibodies or glycan ligands results in programmed cell death in human neutrophils. Intriguingly, the administration of Siglec-E antibody abolished the recruitment of neutrophils in mouse models of neutrophilic pulmonary inflammation in vivo. Given that neutrophils are probably a major culprit in the generation and perpetuation of inflammation, targeting Siglec-9 could be beneficial for the treatment of severe asthma, chronic obstructive pulmonary disease, and related pulmonary disorders characteristic of neutrophilia.

The Role of Heat Shock Protein 70 kDa in Asthma

“…Siglec-5 and Siglec-9 are thought to be inhibitory, while Siglec-14 is an activator that induces the production of IL-8 and TNF-α upon interaction with sialic acid. [48][49][50] In accordance with this concept, the regulation of airway inflammation through the interaction of HSP70 with Siglecs has been demonstrated. Particularly, HSP70 stimulation through Siglec-5 acts as an anti-inflammatory signal, while stimulation through Siglec-14 is proinflammatory.…”

“…38 Several Siglecs have been implicated in the pathogenesis of asthma, particularly Siglec-8 (Siglec-F in mice) in allergic asthma, and Siglec-9 in severe neutrophilic asthma. [48][49][50] Neutrophils also express Siglec-5 and Siglec-14, both of which reportedly bind HSP70. Siglec-5 and Siglec-9 are thought to be inhibitory, while Siglec-14 is an activator that induces the production of IL-8 and TNF-α upon interaction with sialic acid.…”

Severe refractory asthma: current treatment options and ongoing research

“…The airway epithelium has been shown to play a central role in the modulation of complex inflammatory processes. 91 , 92 The cytokines produced by the epithelium can be released following the exposure to pro-inflammatory external stimuli. Among these cytokines, the triad IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) promotes immune responses and are involved in delaying the asthmatic reactions after exposure to allergens.…”

Siglecs as Therapeutic Targets in Cancer

“…Siglec-9 are highly homologous to Siglec-7 (V-set domain ~80% sequence identity), are MHC class I-independent inhibitory receptors, and are similarly found in myeloid cells, NK cells, and a subgroup of PD-1 + CD8 + T cells to resolve ongoing inflammation [102][103][104]. Siglec-9 also binds to a broader spectrum of sialoglycans, recognizes Sia-self-associated molecular patterns (Sia-SAMPs), and transduces Siglec-mediated cell apoptosis of leukocytes [105,106].…”