Table 3. Potential future therapeutic targets in type-2 low asthma.
| Pathway | Pathobiological Mechanism | Potential Biomarkers | Potential Therapeutics |
|---|---|---|---|
| IL-1β | Activation of the NLRP3 inflammasome → NF-kB → cytokines including IL-1β and neutrophil chemokines | IL-1β | Anti-IL-1β (e.g. canakinumab) |
| IL-1R | IL-1β receptor antagonists (e.g. anakinra) | ||
| NLPR3 | NLRP3 small-molecule inhibitors IL-17A, IL-17F | ||
|
| |||
| IL-17A/F | Th17 / γδ T17 / ILC3 / MAIT cells → IL-17A & IL-17F → epithelial derived neutrophil chemoattractants and antimicrobial defence | IL-17A, IL-17F | Anti-IL-17RA (e.g. brodalumab) |
| IL-23A | Anti-IL-23 (e.g. risankizumab) | ||
| RORγt | DNAzymes | ||
| Small-molecule inhibitors | |||
|
| |||
| Alarmins | Epithelial tissue damage → release of alarmins TSLP / IL-33 / IL-25 | Anti-TSLP (e.g. tezepelumab) | |
|
| |||
| Resolvins | Lipoxin A4 promotes resolution of inflammation via ALX/FPR2 | Low LXA4 | LXA4 or analogues |
| Increased serum amyloid A inhibits resolvin signalling via ALX/FPR2 | High SAA | Specialized proresolving mediator precursors | |
|
| |||
| Colony stimulating factors | Apoliporoteins (e.g. APOA1) → ABCA1 inhibit G-CSF-induced neutrophilia | G-CSF | Neutralising antibodies |
| GM-CSF | APOA1 mimetic peptide | ||
|
| |||
| Type I interferons | Stable state: high ISG → type-2-independent inflammation | Blood ISG expression | |
| Acute viral infection: deficient type-I/III IFN → increased viral replication | Low IFN-α / -β / -λ | Inhaled IFN-β | |
|
| |||
| IL-6 | IL-6: obesity / granulocytes → IL-6 → steroid-resistant inflammation | IL-6 | Anti-IL-6 (e.g. clazakizumab) |
| Anti-IL-6R (e.g. tocilizumab) | |||
| IL-6 trans-signalling: bacteria → TLRs → granulocytes shed soluble IL-6R + IL-6 → local epithelial cell inflammation | sIL-6R | Antimicrobials | |
|
| |||
| Mast cells | IgE cross-linking → Mast cell degranulation → mediators including histamine, tryptase, chymase, carboxypeptidase | Tryptase | Anti-β-tryptase mAb |
| Chymase | KIT inhibitors (e.g. imatinib) | ||
|
| |||
| IFN-γ | Th1 / ILC1 / NK cells → IFN-γ → CXCL10 → neutrophilia & ↓ SLPI | TNF | Soluble TNFR (e.g. etanercept) IFN-γ, CXCL10, SLPI |
| IFN-γ, CXCL10, SLPI | Small-molecule inhibtors (JAK1) | ||
| Tbet | DNAzyme (Tbet) | ||
|
| |||
| CXCL8 (IL-8) | CXCL8 → CXCR2 → neutrophil recruitment | CXCL8 | Small-molecule inhibitors |
APOA1, apolipoprotein A1; BET, bromodomain and extraterminal; CXCL, C-X-C motif chemokine ligand; CXCR, C-X-C motif chemokine receptor; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte/monocyte colony-stimulating factor; IFN, interferon; IL, interleukin; ILC, innate lymphoid cell; ISG, interferon-stimulated genes; JAK, Janus kinase; KIT, KIT proto-oncogene receptor tyrosine kinase; LXA, lipoxin A; mAb, monoclonal antibody; NLRP3, nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing; RORγt, retinoic acid-related orphan receptor γ thymus specific; SAA, serum amyloid A; SLPI, secretory leukocyte protease inhibitor; Tbet, T-box transcription factor TBX21; Th1, Th17, helper T-cell type 1 and type 17; TNF, tumour necrosis factor; TSLP, thymic stromal lymphopoietin.